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Actin is a
family In human society A society is a Social group, group of individuals involved in persistent Social relation, social interaction, or a large social group sharing the same spatial or social territory, typically subject to the same Politic ...
of globular multi-functional
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s that form
microfilament Actin cytoskeleton of mouse embryo fibroblasts, stained with Fluorescein isothiocyanate-phalloidin, 250px Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cell (biology), cells that form part of the ...
s. It is found in essentially all
eukaryotic cells Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryotic cells
, where it may be present at a concentration of over 100 μM; its mass is roughly 42-
kDa The dalton or unified atomic mass unit (symbols: Da or u) is a unit Unit may refer to: Arts and entertainment * UNIT, a fictional military organization in the science fiction television series ''Doctor Who'' * Unit of action, a discrete piece of ...
, with a diameter of 4 to 7 nm. An actin protein is the
monomer In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during a ...

monomer
ic subunit of two types of filaments in cells:
microfilaments Actin cytoskeleton of mouse embryo fibroblasts, stained with Fluorescein isothiocyanate-phalloidin, 250px Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cell (biology), cells that form part of the ...

microfilaments
, one of the three major components of the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

cytoskeleton
, and thin filaments, part of the
contractile
contractile
apparatus in
muscle Skeletal muscles (commonly referred to as muscles) are organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's tissues can be broadly cat ...

muscle
cells. It can be present as either a free
monomer In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during a ...

monomer
called G-actin (globular) or as part of a linear
polymer A polymer (; Greek ''poly- Poly, from the Greek :wikt:πολύς, πολύς meaning "many" or "much", may refer to: Businesses * China Poly Group Corporation, a Chinese business group, and its subsidiaries: ** Poly Property, a Hong Kong inc ...

polymer
microfilament called F-actin (filamentous), both of which are essential for such important cellular functions as the
mobility Mobility may refer to: Social sciences and humanities * Economic mobility, ability of individuals or families to improve their economic status * Geographic mobility, the measure of how populations and goods move over time * Mobilities, a contempo ...

mobility
and contraction of
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse lives * Prison cell, a room used to hold peopl ...
during
cell division Cell division is the process by which a parent cell (biology), cell divides into two or more daughter cells. Cell division usually occurs as part of a larger cell cycle. In eukaryotes, there are two distinct types of cell division; a vegetative ...

cell division
. Actin participates in many important cellular processes, including
muscle contraction Muscle contraction is the activation of tension Tension may refer to: Science * Psychological stress * Tension (physics), a force related to the stretching of an object (the opposite of compression) * Tension (geology), a stress which stretches ...
, cell
motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with Sessility (motility), sessility, the ...

motility
, cell division and
cytokinesis Cytokinesis () is the part of the cell division biological process, process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of Mitosis, nuclear di ...

cytokinesis
,
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry) s in an aqueous An aqueous solution is a solution Image:SaltInWaterSolutionLiquid.jpg, Making a saline water solution by dissolving Salt, table salt ...
and
organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, ...
movement,
cell signaling In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms ...
, and the establishment and maintenance of
cell junction Cell junctions (or intercellular bridges) are a class of cellular structures consisting of multiprotein complexes Protein quaternary structure is the number and arrangement of multiple folded protein subunit 274px, Rendering of HLA-A11 showing t ...
s and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with
cellular membranes
cellular membranes
. In vertebrates, three main groups of actin
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystal ...

isoforms
,
alpha Alpha (uppercase , lowercase ; grc, ἄλφα, ''álpha'', modern pronunciation ''álfa'') is the first letter Letter, letters, or literature may refer to: Characters typeface * Letter (alphabet) A letter is a segmental symbol A s ...
,
beta Beta (, ; uppercase , lowercase , or cursive Cursive (also known as script, among other names) is any style of penmanship Penmanship is the technique of writing Writing is a medium of human communication that involves the represen ...
, and
gamma Gamma (uppercase , lowercase ; ''gámma'') is the third letter of the Greek alphabet. In the system of Greek numerals it has a value of 3. In Ancient Greek, the letter gamma represented a voiced velar stop . In Modern Greek, this letter rep ...
have been identified. The alpha actins, found in muscle tissues, are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

cytoskeleton
, and as mediators of internal cell
motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with Sessility (motility), sessility, the ...

motility
. It is believed that the diverse range of structures formed by actin enabling it to fulfill such a large range of functions is regulated through the binding of tropomyosin along the filaments. A cell's ability to dynamically form microfilaments provides the scaffolding that allows it to rapidly remodel itself in response to its environment or to the organism's internal signals, for example, to increase cell membrane absorption or increase
cell adhesion 300px, Schematic of cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces ...
in order to form cell
tissue Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a specific function * ''Triphosa haesitata'', a species of geometer moth found in North America * ''Triphosa dubitata'', a species of geometer mot ...
. Other enzymes or
organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, ...
s such as
cilia The cilium (; the plural is cilia) is an organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, ...
can be anchored to this scaffolding in order to control the deformation of the external
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane A biological membrane, biomembrane or cell membrane is a selectively permeable membra ...

cell membrane
, which allows
endocytosis Endocytosis is a in which are brought into the cell. The material to be internalized is surrounded by an area of , which then buds off inside the cell to form a containing the ingested material. Endocytosis includes (cell drinking) and (cell ...

endocytosis
and
cytokinesis Cytokinesis () is the part of the cell division biological process, process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of Mitosis, nuclear di ...

cytokinesis
. It can also produce movement either by itself or with the help of
molecular motors is a biological machine that utilizes protein dynamics Molecular motors are natural (biological) or artificial molecular machines that are the essential agents of movement in living organisms. In general terms, a Engine, motor is a device that ...
. Actin therefore contributes to processes such as the intracellular transport of
vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features of ...
and organelles as well as
muscular contraction Muscle contraction is the activation of tension-generating sites within muscle fiber Skeletal muscle (also called striated muscle - although cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of verteb ...

muscular contraction
and
cellular migrationCell migration is a central process in the development and maintenance of multicellular organism Multicellular organisms are organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individua ...

cellular migration
. It therefore plays an important role in
embryogenesis An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms ar ...

embryogenesis
, the healing of wounds, and the invasivity of
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolo ...

cancer
cells. The evolutionary origin of actin can be traced to
prokaryotic cells A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual conti ...
, which have equivalent proteins. Actin homologs from prokaryotes and archaea polymerize into different helical or linear filaments consisting of one or multiple strands. However the in-strand contacts and nucleotide binding sites are preserved in prokaryotes and in archaea. Lastly, actin plays an important role in the control of
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...

gene expression
. A large number of illnesses and diseases are caused by
mutation In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...
s in
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is one of two, or more, forms of a given gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance ...
s of the
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
s that regulate the production of actin or of its associated proteins. The production of actin is also key to the process of
infection An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host A host is a person responsible for guests at an event or for providing hospitality during it. Host may ...

infection
by some
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory ...
ic
microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes ...
s. Mutations in the different genes that regulate actin production in humans can cause muscular diseases, variations in the size and function of the
heart The heart is a muscular MUSCULAR (DS-200B), located in the United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain,Usage is mixed. The Guardian' and Telegraph' use ...

heart
as well as
deafness Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss Hearing loss is a partial or total inability to hear Hearing, or auditory perception, is the ability ...
. The make-up of the cytoskeleton is also related to the pathogenicity of intracellular
bacteria Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typ ...

bacteria
and
virus A virus is a submicroscopic infectious agent In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecu ...

virus
es, particularly in the processes related to evading the actions of the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
.


Discovery and early investigation

Actin was first observed
experiment An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into Causality, cause-and-effect by demonstrating what outcome oc ...

experiment
ally in 1887 by W.D. Halliburton, who extracted a protein from muscle that 'coagulated' preparations of
myosin Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...

myosin
that he called "myosin-ferment". However, Halliburton was unable to further refine his findings, and the discovery of actin is credited instead to Brunó Ferenc Straub, a young
biochemist Biochemists are scientists who are trained in biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science (from the Latin Latin (, or , ) is a classical language belonging to the Ital ...

biochemist
working in
Albert Szent-Györgyi Albert Szent-Györgyi de Nagyrápolt (September 16, 1893 – October 22, 1986) was a Hungarian biochemist Biochemists are scientists who are trained in biochemistry Biochemistry or biological chemistry, is the study of chemical proces ...
's laboratory at the Institute of Medical Chemistry at the
University of Szeged The University of Szeged ( hu, Szegedi Tudományegyetem, ) is a Public university, public research university in Szeged, Hungary. Established as the Jesuit Academy of Kolozsvár in present-day Cluj-Napoca in 1581, the institution was re-establishe ...
,
Hungary Hungary ( hu, Magyarország ) is a in . Spanning of the , it is bordered by to the north, to the northeast, to the east and southeast, to the south, and to the southwest and to the west. Hungary has a population of 10 million, mostl ...

Hungary
. Following up on the discovery of Ilona Banga & Szent-Györgyi in 1941 that the coagulation only occurs in some mysosin extractions and was reversed upon the addition of ATP, Straub identified and purified actin from those myosin preparations that did coagulate. Building on Banga's original extraction method, he developed a novel technique for extracting muscle protein that allowed him to isolate substantial amounts of relatively
pure Pure may refer to: Computing * A pure function * A virtual function, pure virtual function * PureSystems, a family of computer systems introduced by IBM in 2012 * Pure Software, a company founded in 1991 by Reed Hastings to support the Purify too ...
actin, published in 1942. Straub's method is essentially the same as that used in
laboratories A laboratory (, ; colloquially lab) is a facility that provides controlled conditions in which scientific Science (from the Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-E ...

laboratories
today. Since Straub's protein was necessary to activate the coagulation of myosin, it was dubbed ''actin''. Realizing that Banga's coagulating myosin preparations contained actin as well, Szent-Györgyi called the mixture of both proteins actomyosin. The hostilities of
World War II World War II or the Second World War, often abbreviated as WWII or WW2, was a global war A world war is "a war War is an intense armed conflict between states State may refer to: Arts, entertainment, and media Literatur ...
meant Szent-Gyorgyi was unable to publish his lab's work in
Western Western may refer to: Places *Western, Nebraska, a village in the US *Western, New York, a town in the US *Western Creek, Tasmania, a locality in Australia *Western Junction, Tasmania, a locality in Australia *Western world, countries that ide ...
scientific journal In academic publishing Academic publishing is the subfield of publishing which distributes academic research and scholarship. Most academic work is published in academic journal articles, books or thesis' form. The part of academic written ...
s. Actin therefore only became well known in the West in 1945, when their paper was published as a supplement to the ''Acta Physiologica Scandinavica''. Straub continued to work on actin, and in 1950 reported that actin contains bound
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
and that, during
polymer A polymer (; Greek ''poly- Poly, from the Greek :wikt:πολύς, πολύς meaning "many" or "much", may refer to: Businesses * China Poly Group Corporation, a Chinese business group, and its subsidiaries: ** Poly Property, a Hong Kong inc ...

polymer
ization of the protein into
microfilament Actin cytoskeleton of mouse embryo fibroblasts, stained with Fluorescein isothiocyanate-phalloidin, 250px Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cell (biology), cells that form part of the ...
s, the
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
is
hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile In chemistry, a nucleop ...

hydrolyzed
to and inorganic
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...

phosphate
(which remain bound to the microfilament). Straub suggested that the transformation of ATP-bound actin to ADP-bound actin played a role in muscular contraction. In fact, this is true only in
smooth muscle Smooth muscle is an involuntary non-striated muscle Striated muscle tissue is a muscle tissue Muscle tissue is a soft tissue that composes muscles in animal bodies, and gives rise to muscles' ability to contract. It is also referred to as myo ...

smooth muscle
, and was not supported through experimentation until 2001. The amino acid sequencing of actin was completed by M. Elzinga and co-workers in 1973. The
crystal structure In crystallography Crystallography is the experimental science of determining the arrangement of atoms in crystalline solids (see crystal structure). The word "crystallography" is derived from the Greek language, Greek words ''crystallon'' "co ...

crystal structure
of G-actin was solved in 1990 by Kabsch and colleagues. In the same year, a model for F-actin was proposed by Holmes and colleagues following experiments using co-crystallization with different proteins. The procedure of co-crystallization with different proteins was used repeatedly during the following years, until in 2001 the isolated protein was crystallized along with ADP. However, there is still no high-resolution X-ray structure of F-actin. The crystallization of F-actin was possible due to the use of a
rhodamine Rhodamine core structure Rhodamine is a family of related dyes, a subset of the triarylmethane dye Triarylmethane dyes are synthetic organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally ...
conjugate that impedes polymerization by blocking the amino acid .; Christine Oriol-Audit died in the same year that actin was first crystallized but she was the researcher that in 1977 first crystallized actin in the absence of Actin Binding Proteins (ABPs). However, the resulting crystals were too small for the available technology of the time. Although no high-resolution model of actin's filamentous form currently exists, in 2008 Sawaya's team were able to produce a more exact model of its structure based on multiple crystals of actin dimers that bind in different places. This model has subsequently been further refined by Sawaya and Lorenz. Other approaches such as the use of
cryo-electron microscopy Cryo-TEM image of GroEL suspended in amorphous ice">GroEL.html" ;"title="Cryo-TEM image of GroEL">Cryo-TEM image of GroEL suspended in amorphous ice at × magnification Cryogenic electron microscopy (cryo-EM) is an electron microscopy An el ...
and
synchrotron radiation Synchrotron radiation (also known as magnetobremsstrahlung radiation) is the electromagnetic radiation In physics Physics is the natural science that studies matter, its Elementary particle, fundamental constituents, its Motion (physic ...
have recently allowed increasing resolution and better understanding of the nature of the interactions and conformational changes implicated in the formation of actin filaments.


Structure

Actin's
amino acid sequence Protein primary structure is the Biomolecular structure#Primary structure, linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the Amine, amino-terminal (N) end to the ...

amino acid sequence
is one of the most highly conserved of the proteins as it has changed little over the course of
evolution Evolution is change in the heritable Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, ...

evolution
, differing by no more than 20% in
species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individu ...

species
as diverse as
algae Algae (; singular alga ) is an informal term for a large and diverse group of photosynthetic Photosynthesis is a process used by plants and other organisms to convert Conversion or convert may refer to: Arts, entertainment, and media * Co ...

algae
and
human Humans (''Homo sapiens'') are the most abundant and widespread species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A speci ...

human
s. It is therefore considered to have an optimised
structure A structure is an arrangement and organization of interrelated elements in a material object or system A system is a group of Interaction, interacting or interrelated elements that act according to a set of rules to form a unified whole. ...

structure
. It has two distinguishing features: it is an
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
that slowly
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
, the "universal energy currency" of biological processes. However, the ATP is required in order to maintain its structural integrity. Its efficient structure is formed by an almost unique process. In addition, it is able to carry out more interactions than any other protein, which allows it to perform a wider variety of functions than other proteins at almost every level of cellular life.
Myosin Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...

Myosin
is an example of a protein that bonds with actin. Another example is
villin Villin is a 92.5 kDa The dalton or unified atomic mass unit (symbols: Da or u) is a unit Unit may refer to: Arts and entertainment * UNIT, a fictional military organization in the science fiction television series ''Doctor Who'' * Unit of acti ...
, which can weave actin into bundles or cut the filaments depending on the concentration of
calcium Calcium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical elem ...

calcium
cations in the surrounding medium. Actin is one of the most abundant proteins in
eukaryote Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryote
s, where it is found throughout the cytoplasm. In fact, in
muscle fibres Skeletal muscle (also called striated muscle - although cardiac muscle is also striated) is one of three major muscle types, the others being cardiac muscle and smooth muscle. It is a form of striated muscle tissue which is under the voluntary cont ...
it comprises 20% of total cellular protein by weight and between 1% and 5% in other cells. However, there is not only one type of actin; the
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
s that code for actin are defined as a
gene family A gene family is a set of several similar genes, formed by duplication of a single original gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendelian units of ...
(a family that in plants contains more than 60 elements, including genes and
pseudogene Pseudogenes are nonfunctional segments of DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon ...
s and in humans more than 30 elements). This means that the genetic information of each individual contains instructions that generate actin variants (called
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallo ...
s) that possess slightly different functions. This, in turn, means that eukaryotic organisms
express Express or EXPRESS may refer to: Arts, entertainment, and media Films * ''Express: Aisle to Glory'', a 1998 comedy short film featuring Kal Penn * ''The Express: The Ernie Davis Story'', a 2008 film starring Dennis Quaid Music * Express (album), ...

express
different genes that give rise to: α-actin, which is found in contractile structures; β-actin, found at the expanding edge of cells that use the projection of their cellular structures as their means of mobility; and γ-actin, which is found in the filaments of stress fibres. In addition to the similarities that exist between an organism's isoforms there is also an
evolutionary conservation In evolutionary biology, conserved sequences are identical or similar Sequence (biology), sequences in nucleic acids (DNA sequence, DNA and RNA) or peptide sequence, proteins across species (homology (biology)#Orthology, orthologous sequences), o ...

evolutionary conservation
in the structure and function even between organisms contained in different eukaryotic domains. In
bacteria Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typ ...

bacteria
the actin homologue
MreB MreB is a protein found in bacteria that has been identified as a homologue of actin Actin is a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity ...

MreB
has been identified, which is a protein that is capable of polymerizing into microfilaments; and in
archaea Archaea ( ; singular archaeon ) constitute a domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a pa ...

archaea
the homologue Ta0583 is even more similar to the eukaryotic actins. Cellular actin has two forms: monomeric globules called G-actin and
polymeric A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance Substance may refer to: * Substance (Jainism), a term in Jain ontology to denote the base or owner of attributes * Chemical substance, a material with a definite chemical ...
filaments called F-actin (that is, as filaments made up of many G-actin monomers). F-actin can also be described as a microfilament. Two parallel F-actin strands must rotate 166 degrees to lie correctly on top of each other. This creates the double helix structure of the microfilaments found in the cytoskeleton. Microfilaments measure approximately 7 nm in diameter with the helix repeating every 37 nm. Each molecule of actin is bound to a molecule of
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properti ...

adenosine triphosphate
(ATP) or
adenosine diphosphate Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of o ...

adenosine diphosphate
(ADP) that is associated with a cation. The most commonly found forms of actin, compared to all the possible combinations, are ATP-G-Actin and ADP-F-actin.


G-Actin

Scanning electron microscope A scanning electron microscope (SEM) is a type of electron microscope that produces images of a sample by scanning the surface with a focused beam of electrons. The electrons interact with atoms in the sample, producing various signals that ...
images indicate that G-actin has a globular structure; however,
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract into many specific directions. By measurin ...

X-ray crystallography
shows that each of these globules consists of two lobes separated by a cleft. This structure represents the “ATPase fold”, which is a centre of enzymatic catalysis that binds ATP and Mg2+ and hydrolyzes the former to ADP plus
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...

phosphate
. This fold is a conserved structural motif that is also found in other proteins that interact with triphosphate
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
s such as
hexokinase A hexokinase is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the e ...
(an enzyme used in energy
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life Life is a characteristic that distinguishes physical entities A bubble of exhaled gas in water In common usage and classical mechanics, a phys ...

metabolism
) or in
Hsp70#REDIRECT Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other r ...

Hsp70
proteins (a protein family that play an important part in protein folding). G-actin is only functional when it contains either ADP or ATP in its cleft but the form that is bound to ATP predominates in cells when actin is present in its free state. The
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract into many specific directions. By measurin ...

X-ray crystallography
model of actin that was produced by Kabsch from the
striated muscle tissue Striated muscle tissue is a muscle tissue Muscle tissues are soft tissue of a tendon A tendon or sinew is a tough band of fibrous connective tissue that connects muscle to bone A bone is a Stiffness, rigid tissue (anatomy), tissue that c ...

striated muscle tissue
of
rabbits Rabbits are small mammal Mammals (from Latin language, Latin , 'breast') are a group of vertebrate animals constituting the class (biology), class Mammalia (), and characterized by the presence of mammary glands which in Female#Mammali ...
is the most commonly used in structural studies as it was the first to be purified. The G-actin crystallized by Kabsch is approximately 67 x 40 x 37 in size, has a
molecular mass The molecular mass (''m'') is the mass of a given molecule: it is measured in dalton Dalton may refer to: Science * Dalton (crater), a lunar crater * Dalton (program), chemistry software * Dalton (unit) (Da), the atomic mass unit Entertainmen ...
of 41,785 Da and an estimated
isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the ...
of 4.8. Its net charge at = 7 is -7. ;Primary structure Elzinga and co-workers first determined the complete
peptide sequence Peptides (from Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ), refers collectively to the dialects of the Greek language spoken ...
for this type of actin in 1973, with later work by the same author adding further detail to the model. It contains 374
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
residues. Its
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to hav ...

N-terminus
is highly
acid An acid is a or capable of donating a (hydrogen ion H+) (a ), or, alternatively, capable of forming a with an (a ). The first category of acids are the proton donors, or s. In the special case of , proton donors form the H3O+ and are ...
ic and starts with an
acetyl In organic chemistry Organic chemistry is a branch of that studies the structure, properties and reactions of s, which contain in .Clayden, J.; Greeves, N. and Warren, S. (2012) ''Organic Chemistry''. Oxford University Press. pp. 1–15. . ...

acetyl
ed aspartate in its amino group. While its
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid Amino acids are organic compound In , organic compounds are generally any s that contain ...

C-terminus
is
alkaline In chemistry, an alkali (; from ar, القلوي ''al-qaly'' "ashes of the saltwort") is a base (chemistry), basic, ionic compound, ionic salt (chemistry), salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as ...
and is formed by a
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organ ...

phenylalanine
preceded by a
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the chemical formula, formula HOOC-CH-(NH2)-CH2-SH. The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. The thiol is suscepti ...

cysteine
, which has a degree of functional importance. Both extremes are in close proximity within the I-subdomain. An anomalous is located at position 73. ;Tertiary structure — domains The tertiary structure is formed by two domains known as the large and the small, which are separated by a cleft centred around the location of the bond with
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
-+. Below this there is a deeper notch called a “groove”. In the
native state In biochemistry, the native state of a protein or nucleic acid is its properly folded and/or assembled form, which is operative and functional. The native state of a biomolecule may possess all four levels of biomolecular structure, with the seco ...

native state
, despite their names, both have a comparable depth. The normal convention in
topological s, which have only one surface and one edge, are a kind of object studied in topology. In mathematics Mathematics (from Ancient Greek, Greek: ) includes the study of such topics as quantity (number theory), mathematical structure, structu ...

topological
studies means that a protein is shown with the biggest domain on the left-hand side and the smallest domain on the right-hand side. In this position the smaller domain is in turn divided into two: subdomain I (lower position, residues 1–32, 70–144, and 338–374) and subdomain II (upper position, residues 33–69). The larger domain is also divided in two: subdomain III (lower, residues 145–180 and 270–337) and subdomain IV (higher, residues 181–269). The exposed areas of subdomains I and III are referred to as the “barbed” ends, while the exposed areas of domains II and IV are termed the “pointed" ends. This nomenclature refers to the fact that, due to the small mass of subdomain II actin is polar; the importance of this will be discussed below in the discussion on assembly dynamics. Some authors call the subdomains Ia, Ib, IIa, and IIb, respectively. ;Other important structures The most notable supersecondary structure is a five chain
beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif Motif may refer to: General concepts * Motif (chess composition), an element of a move in the consideration of its purpose * Motif (folkloristics), a recurring element that cre ...
that is composed of a β-meander and a β-α-β clockwise unit. It is present in both domains suggesting that the protein arose from gene duplication. * The binding site is located between two
beta hairpin The beta hairpin (sometimes also called beta-ribbon or beta-beta unit) is a simple protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , p ...

beta hairpin
-shaped structures pertaining to the I and III domains. The residues that are involved are Asp11-Lys18 and Asp154-His161 respectively. * The
divalent cation In chemistry, the valence or valency of an chemical element, element is the measure of its combining capacity with other atoms when it forms chemical compounds or molecules. Description The combining capacity, or affinity of an atom of a given e ...
binding site is located just below that for the adenosine nucleotide. ''In vivo'' it is most often formed by or while ''in vitro'' it is formed by a chelating structure made up of and two
oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the chemical elements In chemistry, an element is a pure substance consisting only of atoms that all have the same ...

oxygen
s from the nucleotide's α-and β-
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...

phosphate
s. This calcium is coordinated with six water molecules that are retained by the amino acids Asp11, Asp154, and . They form a complex with the nucleotide that restricts the movements of the so-called "hinge" region, located between residues 137 and 144. This maintains the native form of the protein until its withdrawal denatures the actin monomer. This region is also important because it determines whether the protein's cleft is in the "open" or "closed" conformation. * It is highly likely that there are at least three other centres with a lesser
affinity Affinity may refer to: Commerce, finance and law * Affinity (law) In law and in cultural anthropology Cultural anthropology is a branch of anthropology Anthropology is the scientific study of human Humans (''Homo sapiens' ...
(intermediate) and still others with a low affinity for divalent cations. It has been suggested that these centres may play a role in the polymerization of actin by acting during the activation stage. * There is a structure in subdomain 2 that is called the “D-loop” because it binds with
DNase I Deoxyribonuclease I (usually called DNase I), is an endonucleaseEndonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (without regard to se ...
, it is located between the and residues. It has the appearance of a disorderly element in the majority of crystals, but it looks like a β-sheet when it is complexed with DNase I. It has been proposed that the key event in polymerization is probably the propagation of a conformational change from the centre of the bond with the nucleotide to this domain, which changes from a loop to a spiral. However, this hypothesis has been refuted by other studies.


F-Actin

The classical description of F-actin states that it has a filamentous structure that can be considered to be a single stranded levorotatory
helix A helix (), plural helixes or helices (), is a shape like a corkscrew or spiral staircase. It is a type of smooth Smooth may refer to: Mathematics * Smooth function is a smooth function with compact support. In mathematical analysis, the ...

helix
with a rotation of 166° around the helical axis and an axial translation of 27.5 , or a single stranded
dextrorotatory Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization Polarization or polarisation may refer to: In the physical sciences *Polarization (waves), the abi ...
helix with a cross over spacing of 350–380 Å, with each actin surrounded by four more. The symmetry of the actin polymer at 2.17 subunits per turn of a helix is incompatible with the formation of
crystal A crystal or crystalline solid is a solid Solid is one of the four fundamental states of matter (the others being liquid A liquid is a nearly incompressible fluid In physics, a fluid is a substance that continually Deformatio ...

crystal
s, which is only possible with a symmetry of exactly 2, 3, 4 or 6 subunits per turn. Therefore, models have to be constructed that explain these anomalies using data from
electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hig ...

electron microscopy
,
cryo-electron microscopy Cryo-TEM image of GroEL suspended in amorphous ice">GroEL.html" ;"title="Cryo-TEM image of GroEL">Cryo-TEM image of GroEL suspended in amorphous ice at × magnification Cryogenic electron microscopy (cryo-EM) is an electron microscopy An el ...
, crystallization of dimers in different positions and . It should be pointed out that it is not correct to talk of a “structure” for a molecule as dynamic as the actin filament. In reality we talk of distinct structural states, in these the measurement of axial translation remains constant at 27.5 Å while the subunit rotation data shows considerable variability, with displacements of up to 10% from its optimum position commonly seen. Some proteins, such as
cofilin ADF/cofilin is a family of actin-binding proteinActin-binding proteins (also known as ABPs) are proteins that bind to actin Actin is a family In human society, family (from la, familia) is a group of people related either by consangui ...
appear to increase the angle of turn, but again this could be interpreted as the establishment of different structural states. These could be important in the polymerization process. There is less agreement regarding measurements of the turn radius and filament thickness: while the first models assigned a length of 25 Å, current X-ray diffraction data, backed up by cryo-electron microscopy suggests a length of 23.7 Å. These studies have shown the precise contact points between monomers. Some are formed with units of the same chain, between the "barbed" end on one monomer and the "pointed" end of the next one. While the monomers in adjacent chains make lateral contact through projections from subdomain IV, with the most important projections being those formed by the C-terminus and the hydrophobic link formed by three bodies involving residues 39–42, 201–203, and 286. This model suggests that a filament is formed by monomers in a "sheet" formation, in which the subdomains turn about themselves, this form is also found in the bacterial actin homologue
MreB MreB is a protein found in bacteria that has been identified as a homologue of actin Actin is a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity ...

MreB
. The F-actin polymer is considered to have structural polarity due to the fact that all the microfilament's subunits point towards the same end. This gives rise to a naming convention: the end that possesses an actin subunit that has its ATP binding site exposed is called the "(-) end", while the opposite end where the cleft is directed at a different adjacent monomer is called the "(+) end". The terms "pointed" and "barbed" referring to the two ends of the microfilaments derive from their appearance under
transmission electron microscopy #REDIRECT Transmission electron microscopy Transmission electron microscopy (TEM) is a technique in which a beam of s is transmitted through a specimen to form an image. The specimen is most often an ultrathin section less than 100 nm thic ...
when samples are examined following a preparation technique called "decoration". This method consists of the addition of
myosin Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...

myosin
S1 fragments to tissue that has been fixed with
tannic acid Tannic acid is a specific form of tannin Tannins (or tannoids) are a class of , ic s that bind to and s and various other organic compounds including s and s. The term ''tannin'' (from ''tanner'', from ''tannāre'', from ''tannum'' ...

tannic acid
. This myosin forms polar bonds with actin monomers, giving rise to a configuration that looks like arrows with feather fletchings along its shaft, where the shaft is the actin and the fletchings are the myosin. Following this logic, the end of the microfilament that does not have any protruding myosin is called the point of the arrow (- end) and the other end is called the barbed end (+ end). A S1 fragment is composed of the head and neck domains of
myosin II Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...
. Under physiological conditions, G-actin (the
monomer In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during a ...

monomer
form) is transformed to F-actin (the
polymer A polymer (; Greek ''poly- Poly, from the Greek :wikt:πολύς, πολύς meaning "many" or "much", may refer to: Businesses * China Poly Group Corporation, a Chinese business group, and its subsidiaries: ** Poly Property, a Hong Kong inc ...

polymer
form) by ATP, where the role of ATP is essential. The helical F-actin filament found in muscles also contains a
tropomyosin Tropomyosin is a two-stranded alpha-helical, coiled coil A coiled coil is a structural motif In a polymer, chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that ...

tropomyosin
molecule, which is a 40
nanometre file:EM Spectrum Properties edit.svg, 330px, Different lengths as in respect to the Electromagnetic spectrum, measured by the Metre and its derived scales. The nanometre is often used to express dimensions on an atomic scale and mostly in the Mo ...
long protein that is wrapped around the F-actin helix. During the resting phase the tropomyosin covers the actin's active sites so that the actin-myosin interaction cannot take place and produce muscular contraction. There are other protein molecules bound to the tropomyosin thread, these are the
troponin image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL Troponin, or ...
s that have three polymers:
troponin I Troponin I is a cardiac and skeletal muscle protein family. It is a part of the troponin protein complex, where it binds to actin in thin myofilaments to hold the actin-tropomyosin complex in place. Troponin I prevents myosin from binding to actin ...
,
troponin T Troponin T (shortened TnT or TropT) is a part of the troponin image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = trop ...
, and
troponin C Troponin C is a protein which is part of the troponin image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; ma ...
.


Folding

Actin can spontaneously acquire a large part of its
tertiary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an elect ...
. However, the way it acquires its from its newly
synthesized Synthesis or synthesize may also refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of or ...

synthesized
native form is special and almost unique in protein chemistry. The reason for this special route could be the need to avoid the presence of incorrectly folded actin monomers, which could be toxic as they can act as inefficient polymerization terminators. Nevertheless, it is key to establishing the stability of the cytoskeleton, and additionally, it is an essential process for coordinating the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication In , DNA replication is the of pro ...

cell cycle
. CCT is required in order to ensure that folding takes place correctly. CCT is a group II chaperonin, a large protein complex that assists in the folding of other proteins. CCT is formed of a double ring of eight different subunits (hetero-octameric) and it differs from group I chaperonins like
GroEL GroEL is a protein which belongs to the family of , and is found in many bacteria. It is required for the proper of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex . In the proteins Hsp60 and Hsp1 ...

GroEL
, which is found in Eubacteria and in eukaryotic organelles, as it does not require a co-chaperone to act as a lid over the central
catalytic that utilizes a low-temperature oxidation catalyst to convert carbon monoxide to less toxic carbon dioxide Carbon dioxide (chemical formula ) is a colorless gas with a density about 53% higher than that of dry air. Carbon dioxide molecules ...

catalytic
cavity. Substrates bind to CCT through specific domains. It was initially thought that it only bound with actin and
tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular protein 300px, 3-dimensional structure of hemoglobin, a globular protein. Globular proteins or spheroproteins are spherical ("globe-like") protein ...

tubulin
, although recent
immunoprecipitation Immunoprecipitation (IP) is the technique of precipitating a protein antigen In immunology, an antigen (Ag) is a molecule or molecular structure, such as may be present on the outside of a pathogen, that can be bound by an antigen-specific a ...

immunoprecipitation
studies have shown that it interacts with a large number of
polypeptide Peptides (from Greek language πεπτός, ''peptós'' "digested"; derived from πέσσειν, ''péssein'' "to digest") are short chains of amino acids linked by peptide bonds. Chains of fewer than ten or fifteen amino acids are called oligope ...
s, which possibly function as substrates. It acts through ATP-dependent conformational changes that on occasion require several rounds of liberation and catalysis in order to complete a reaction. In order to successfully complete their folding, both actin and tubulin need to interact with another protein called , which is a heterohexameric complex (formed by six distinct subunits), in an interaction that is so specific that the molecules have coevolved. Actin complexes with prefoldin while it is still being formed, when it is approximately 145
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s long, specifically those at the N-terminal. Different recognition sub-units are used for actin or tubulin although there is some overlap. In actin the subunits that bind with prefoldin are probably PFD3 and PFD4, which bind in two places one between residues 60–79 and the other between residues 170–198. The actin is recognized, loaded, and delivered to the cytosolic chaperonin (CCT) in an open conformation by the inner end of prefoldin's "tentacles” (see the image and note). The contact when actin is delivered is so brief that a tertiary complex is not formed, immediately freeing the prefoldin. The CCT then causes actin's sequential folding by forming bonds with its subunits rather than simply enclosing it in its cavity. This is why it possesses specific recognition areas in its apical β-domain. The first stage in the folding consists of the recognition of residues 245–249. Next, other determinants establish contact. Both actin and tubulin bind to CCT in open conformations in the absence of ATP. In actin's case, two subunits are bound during each conformational change, whereas for tubulin binding takes place with four subunits. Actin has specific binding sequences, which interact with the δ and β-CCT subunits or with δ-CCT and ε-CCT. After AMP-PNP is bound to CCT the substrates move within the chaperonin's cavity. It also seems that in the case of actin, the CAP protein is required as a possible cofactor in actin's final folding states. The exact manner by which this process is regulated is still not fully understood, but it is known that the protein PhLP3 (a protein similar to
phosducin Phosducin, also known as PDC, is a human protein and gene. It belongs to the phosducin family of proteins. This gene encodes a phosphoprotein, which is located in the outer and inner segments of the rod cells in the retina. This protein may partici ...
) inhibits its activity through the formation of a tertiary complex.


ATPase’s catalytic mechanism

Actin is an
ATPase ATPases (, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, adenosine 5'-triphosphatase, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
, which means that it is an
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
that
hydrolyzes Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

hydrolyzes
ATP. This group of enzymes is characterised by their slow reaction rates. It is known that this ATPase is “active”, that is, its speed increases by some 40,000 times when the actin forms part of a filament. A reference value for this rate of hydrolysis under ideal conditions is around 0.3 s−1. Then, the Pi remains bound to the actin next to the ADP for a long time, until it is cooperatively liberated from the interior of the filament. The exact molecular details of the catalytic mechanism are still not fully understood. Although there is much debate on this issue, it seems certain that a "closed" conformation is required for the hydrolysis of ATP, and it is thought that the residues that are involved in the process move to the appropriate distance. The
glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compound ...
Glu137 is one of the key residues, which is located in subdomain 1. Its function is to bind the water molecule that produces a
nucleophilic attack In chemistry, a nucleophile is a chemical species that forms bonds with Electrophile, electrophiles by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophi ...

nucleophilic attack
on the ATP's γ-phosphate
bond Bond or bonds may refer to: Common meanings * Bond (finance) In finance Finance is the study of financial institutions, financial markets and how they operate within the financial system. It is concerned with the creation and management of ...
, while the nucleotide is strongly bound to subdomains 3 and 4. The slowness of the catalytic process is due to the large distance and skewed position of the water molecule in relation to the reactant. It is highly likely that the conformational change produced by the rotation of the domains between actin's G and F forms moves the Glu137 closer allowing its hydrolysis. This model suggests that the polymerization and ATPase's function would be decoupled straight away. The "open" to "closed" transformation between G and F forms and its implications on the relative motion of several key residues and the formation of water wires have been characterized in
molecular dynamics Molecular dynamics (MD) is a computer simulation Computer simulation is the process of mathematical modelling, performed on a computer, which is designed to predict the behaviour of, or the outcome of, a real-world or physical system. Th ...
and
QM/MM The hybrid QM/MM (quantum mechanics/molecular mechanics) approach is a molecular simulation method that combines the strengths of Ab initio quantum chemistry methods, ''ab initio'' QM calculations (accuracy) and MM (speed) approaches, thus allowing ...
simulations.


Genetics

Actin has been one of the most highly conserved proteins throughout evolution because it interacts with a large number of other proteins. It has 80.2% sequence
conservation Conservation is the preservation or efficient use of resources, or the conservation of various quantities under physical laws. Conservation may also refer to: Environment and natural resources * Nature conservation, the protection and manageme ...
at the
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
level between ''
Homo sapiens Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedality, bipedalism and large, complex brains. This has enabled the development of advanced tools, culture, and language. Humans are highl ...

Homo sapiens
'' and ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () is a species of yeast Yeasts are eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are ...

Saccharomyces cerevisiae
'' (a species of yeast), and 95% conservation of the
primary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon ...

primary structure
of the protein product. Although most
yeast Yeasts are eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular ...

yeast
s have only a single actin gene, higher
eukaryote Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryote
s, in general,
express Express or EXPRESS may refer to: Arts, entertainment, and media Films * ''Express: Aisle to Glory'', a 1998 comedy short film featuring Kal Penn * ''The Express: The Ernie Davis Story'', a 2008 film starring Dennis Quaid Music * Express (album), ...

express
several
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallo ...
s of actin encoded by a family of related genes.
Mammal Mammals (from Latin Latin (, or , ) is a classical language A classical language is a language A language is a structured system of communication Communication (from Latin ''communicare'', meaning "to share" or "to be i ...
s have at least six actin isoforms coded by separate genes, which are divided into three classes (alpha,
beta Beta (, ; uppercase , lowercase , or cursive Cursive (also known as script, among other names) is any style of penmanship Penmanship is the technique of writing Writing is a medium of human communication that involves the represen ...
, and gamma) according to their
isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the ...
s. In general, alpha actins are found in muscle (α-skeletal, α-aortic smooth, α-cardiac), whereas beta and gamma isoforms are prominent in non-muscle cells (β-cytoplasmic, γ1-cytoplasmic, γ2-enteric smooth). Although the amino acid sequences and ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applie ...

in vitro
'' properties of the isoforms are highly similar, these isoforms cannot completely substitute for one another ''
in vivo Studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series ...
''. The typical actin gene has an approximately 100-nucleotide
5' UTR The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly Upstream and downstream (DNA), upstream from the initiation codon. This region is im ...
, a 1200-nucleotide
translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
region, and a 200-nucleotide
3' UTR In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation (biology), translation termination codon. The 3′-UTR often contains regulatory regions that Po ...
. The majority of actin genes are interrupted by
intron An intron (for ''intragenic region'') is any Nucleic acid sequence, nucleotide sequence within a gene that is removed by RNA splicing during Post-transcriptional modification, maturation of the final RNA product. In other words, introns are non-c ...

intron
s, with up to six introns in any of 19 well-characterised locations. The high conservation of the family makes actin the favoured model for studies comparing the introns-early and introns-late models of intron evolution. All non-spherical
prokaryote A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual conti ...
s appear to possess genes such as
MreB MreB is a protein found in bacteria that has been identified as a homologue of actin Actin is a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity ...

MreB
, which encode homologues of actin; these genes are required for the cell's shape to be maintained. The
plasmid A plasmid is a small, extrachromosomal DNA Extrachromosomal DNA (abbreviated ecDNA) is any DNA that is found off the chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. Most eukaryo ...
-derived gene ParM encodes an actin-like protein whose polymerized form is , and appears to partition the plasmid
DNA Deoxyribonucleic acid (; DNA) is a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical ...

DNA
into its daughter cells during cell division by a mechanism analogous to that employed by microtubules in eukaryotic
mitosis In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proce ...

mitosis
. Actin is found in both smooth and rough endoplasmic reticulums.


Assembly dynamics


Nucleation and polymerization

Nucleating factors are necessary to stimulate actin polymerization. One such nucleating factor is the
Arp2/3 complex Arp2/3 complex (Actin Related Protein 2/3 complex) is a seven-subunit protein complex that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the microfilament, actin cytoskeleton and is found in most actin ...
, which mimics a G-actin dimer in order to stimulate the nucleation (or formation of the first trimer) of monomeric G-actin. The
Arp2/3 complex Arp2/3 complex (Actin Related Protein 2/3 complex) is a seven-subunit protein complex that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the microfilament, actin cytoskeleton and is found in most actin ...
binds to actin filaments at 70 degrees to form new actin branches off existing actin filaments. Arp2/3-mediated nucleation is necessary for directed cell migration. Also, actin filaments themselves bind ATP, and hydrolysis of this ATP stimulates destabilization of the polymer. The growth of actin filaments can be regulated by thymosin and profilin. Thymosin binds to G-actin to buffer the polymerizing process, while profilin binds to G-actin to exchange Adenosine diphosphate, ADP for
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
, promoting the monomeric addition to the barbed, plus end of F-actin filaments. F-actin is both Strength of materials, strong and dynamic. Unlike other
polymer A polymer (; Greek ''poly- Poly, from the Greek :wikt:πολύς, πολύς meaning "many" or "much", may refer to: Businesses * China Poly Group Corporation, a Chinese business group, and its subsidiaries: ** Poly Property, a Hong Kong inc ...

polymer
s, such as
DNA Deoxyribonucleic acid (; DNA) is a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical ...

DNA
, whose constituent elements are bound together with covalent bonds, the monomers of actin filaments are assembled by weaker bonds. The lateral bonds with neighbouring monomers resolve this anomaly, which in theory should weaken the structure as they can be broken by thermal agitation. In addition, the weak bonds give the advantage that the filament ends can easily release or incorporate monomers. This means that the filaments can be rapidly remodelled and can change cellular structure in response to an environmental stimulus. Which, along with the biochemical mechanism by which it is brought about is known as the "assembly dynamic". ; ''In vitro'' studies Studies focusing on the accumulation and loss of subunits by microfilaments are carried out ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applie ...

in vitro
'' (that is, in the laboratory and not on cellular systems) as the polymerization of the resulting actin gives rise to the same F-actin as produced ''
in vivo Studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series ...
''. The ''in vivo'' process is controlled by a multitude of proteins in order to make it responsive to cellular demands, this makes it difficult to observe its basic conditions. ''In vitro'' production takes place in a sequential manner: first, there is the "activation phase", when the bonding and exchange of divalent cations occurs in specific places on the G-actin, which is bound to ATP. This produces a conformational change, sometimes called G*-actin or F-actin monomer as it is very similar to the units that are located on the filament. This prepares it for the "nucleation phase", in which the G-actin gives rise to small unstable fragments of F-actin that are able to polymerize. Unstable dimers and trimers are initially formed. The "elongation phase" begins when there are a sufficiently large number of these short polymers. In this phase the filament forms and rapidly grows through the reversible addition of new monomers at both extremes. Finally, a Chemical equilibrium, stationary equilibrium is achieved where the G-actin monomers are exchanged at both ends of the microfilament without any change to its total length. In this last phase the "critical concentration Cc" is defined as the ratio between the assembly constant and the dissociation constant for G-actin, where the dynamic for the addition and elimination of dimers and trimers does not produce a change in the microfilament's length. Under ''in vitro'' conditions Cc is 0.1 μM, which means that at higher values polymerization occurs and at lower values depolymerization occurs. ;Role of ATP hydrolysis As indicated above, although actin hydrolyzes ATP, everything points to the fact that ATP is not required for actin to be assembled, given that, on one hand, the hydrolysis mainly takes place inside the filament, and on the other hand the ADP could also instigate polymerization. This poses the question of understanding which thermodynamics, thermodynamically unfavourable process requires such a prodigious expenditure of energy. The actin cycle, which couples ATP hydrolysis to actin polymerization, consists of the preferential addition of G-actin-ATP monomers to a filament's barbed end, and the simultaneous disassembly of F-actin-ADP monomers at the pointed end where the ADP is subsequently changed into ATP, thereby closing the cycle. This aspect of actin filament formation is known as “treadmilling”. ATP is hydrolysed relatively rapidly just after the addition of a G-actin monomer to the filament. There are two hypotheses regarding how this occurs; the stochastic, which suggests that hydrolysis randomly occurs in a manner that is in some way influenced by the neighbouring molecules; and the vectorial, which suggests that hydrolysis only occurs adjacent to other molecules whose ATP has already been hydrolysed. In either case, the resulting Pi is not released; it remains for some time noncovalent bonding, noncovalently bound to actin's ADP. In this way there are three species of actin in a filament: ATP-Actin, ADP+Pi-Actin and ADP-Actin. The amount of each one of these species present in a filament depends on its length and state: as elongation commences the filament has an approximately equal amount of actin monomers bound with ATP and ADP+Pi and a small amount of ADP-Actin at the (-) end. As the stationary state is reached the situation reverses, with ADP present along the majority of the filament and only the area nearest the (+) end containing ADP+Pi and with ATP only present at the tip. If we compare the filaments that only contain ADP-Actin with those that include ATP, in the former the critical constants are similar at both ends, while Cc for the other two nucleotides is different: At the (+) end Cc+=0.1 μM, while at the (-) end Cc=0.8 μM, which gives rise to the following situations: * For G-actin-ATP concentrations less than Cc+ no elongation of the filament occurs. * For G-actin-ATP concentrations less than Cc but greater than Cc+ elongation occurs at the (+) end. * For G-actin-ATP concentrations greater than Cc the microfilament grows at both ends. It is therefore possible to deduce that the energy produced by hydrolysis is used to create a true “stationary state”, that is a flux, instead of a simple equilibrium, one that is dynamic, polar, and attached to the filament. This justifies the expenditure of energy as it promotes essential biological functions. In addition, the configuration of the different monomer types is detected by actin binding proteins, which also control this dynamism, as will be described in the following section. Microfilament formation by treadmilling has been found to be atypical in stereocilia. In this case the control of the structure's size is totally apical and it is controlled in some way by gene expression, that is, by the total quantity of protein monomer synthesized in any given moment.


Associated proteins

The actin cytoskeleton ''
in vivo Studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series ...
'' is not exclusively composed of actin, other proteins are required for its formation, continuance, and function. These proteins are called ''actin-binding proteins'' (ABP) and they are involved in actin's polymerization, depolymerization, stability, organisation in bundles or networks, fragmentation, and destruction. The diversity of these proteins is such that actin is thought to be the protein that takes part in the greatest number of protein-protein interactions. For example, G-actin sequestering elements exist that impede its incorporation into microfilaments. There are also proteins that stimulate its polymerization or that give complexity to the synthesizing networks. * Thymosins, Thymosin β-4 is a 5 kDa protein that can bind with G-actin-ATP in a 1:1 stoichiometry; which means that one unit of thymosin β-4 binds to one unit of G-actin. Its role is to impede the incorporation of the monomers into the growing polymer. * Profilin, is a cytosolic protein with a molecular weight of 15 kDa, which also binds with G-actin-ATP or -ADP with a stoichiometry of 1:1, but it has a different function as it facilitates the replacement of ADP nucleotides by ATP. It is also implicated in other cellular functions, such as the binding of proline repetitions in other proteins or of lipids that act as second messenger system, secondary messengers. Other proteins that bind to actin regulate the length of the microfilaments by cutting them, which gives rise to new active ends for polymerization. For example, if a microfilament with two ends is cut twice, there will be three new microfilaments with six ends. This new situation favors the dynamics of assembly and disassembly. The most notable of these proteins are gelsolin and
cofilin ADF/cofilin is a family of actin-binding proteinActin-binding proteins (also known as ABPs) are proteins that bind to actin Actin is a family In human society, family (from la, familia) is a group of people related either by consangui ...
. These proteins first achieve a cut by binding to an actin monomer located in the polymer they then change the actin monomer's Protein conformation, conformation while remaining bound to the newly generated (+) end. This has the effect of impeding the addition or exchange of new G-actin subunits. Depolymerization is encouraged as the (-) ends are not linked to any other molecule. Other proteins that bind with actin cover the ends of F-actin in order to stabilize them, but they are unable to break them. Examples of this type of protein are CapZ, which binds the (+) ends depending on a cell's levels of calcium, Ca2+/calmodulin. These levels depend on the cell's internal and external signals and are involved in the regulation of its biological functions). Another example is tropomodulin (that binds to the (-) end). Tropomodulin basically acts to stabilize the F-actin present in the myofibrils present in
muscle Skeletal muscles (commonly referred to as muscles) are organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's tissues can be broadly cat ...

muscle
sarcomeres, which are structures characterized by their great stability. The
Arp2/3 complex Arp2/3 complex (Actin Related Protein 2/3 complex) is a seven-subunit protein complex that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the microfilament, actin cytoskeleton and is found in most actin ...
is widely found in all Eukaryote, eukaryotic organisms. It is composed of seven subunits, some of which possess a topology that is clearly related to their biological function: two of the subunits, ARP2 and ARP3, have a structure similar to that of actin monomers. This homology allows both units to act as nucleation, nucleation agents in the polymerization of G-actin and F-actin. This complex is also required in more complicated processes such as in establishing dendrite, dendritic structures and also in anastomosis (the reconnection of two branching structures that had previously been joined, such as in blood vessels).


Chemical inhibitors

There are a number of toxins that interfere with actin's dynamics, either by preventing it from polymerizing (latrunculin and cytochalasin D) or by stabilizing it (phalloidin): * Latrunculin is a toxin produced by sponges. It binds to G-actin preventing it from binding with microfilaments. * Cytocalasin D, is an alkaloid produced by fungi, that binds to the (+) end of F-actin preventing the addition of new monomers. Cytocalasin D has been found to disrupt actin's dynamics, activating protein p53 in animals. * Phalloidin, is a toxin that has been isolated from the death cap mushroom ''Amanita phalloides''. It binds to the interface between adjacent actin monomers in the F-actin polymer, preventing its depolymerization.


Functions and location

Actin forms filaments ('F-actin' or
microfilament Actin cytoskeleton of mouse embryo fibroblasts, stained with Fluorescein isothiocyanate-phalloidin, 250px Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cell (biology), cells that form part of the ...
s) are essential elements of the eukaryotic
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

cytoskeleton
, able to undergo very fast polymerization and depolymerization dynamics. In most cells actin filaments form larger-scale networks which are essential for many key functions in cells: * Various types of actin networks (made of actin filaments) give mechanical support to cells, and provide trafficking routes through the cytoplasm to aid signal transduction. * Rapid assembly and disassembly of actin network enables cells to migrate (Cell migration). * In metazoan
muscle Skeletal muscles (commonly referred to as muscles) are organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's tissues can be broadly cat ...

muscle
cells, to be the scaffold on which
myosin Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...

myosin
proteins generate force to support muscle contraction. * In non-muscle cells, to be a track for cargo transport myosins (nonconventional myosins) such as myosin V and VI. Nonconventional myosins use ATP hydrolysis to transport cargo, such as Vesicle (biology), vesicles and organelles, in a directed fashion much faster than diffusion. Myosin V walks towards the barbed end of actin filaments, while myosin VI walks toward the pointed end. Most actin filaments are arranged with the barbed end toward the cellular membrane and the pointed end toward the cellular interior. This arrangement allows myosin V to be an effective motor for the export of cargos, and myosin VI to be an effective motor for import. The actin protein is found in both the cytoplasm and the cell nucleus. Its location is regulated by cell membrane signal transduction pathways that integrate the stimuli that a cell receives stimulating the restructuring of the actin networks in response. In ''Dictyostelium'', phospholipase D has been found to intervene in inositol phosphate pathways. Actin filaments are particularly stable and abundant in myocyte, muscle fibres. Within the sarcomere (the basic morphological and physiological unit of muscle fibres) actin is present in both the I and A bands; myosin is also present in the latter.


Cytoskeleton

Microfilaments are involved in the movement of all mobile cells, including non-muscular types, and drugs that disrupt F-actin organization (such as the cytochalasins) affect the activity of these cells. Actin comprises 2% of the total amount of proteins in hepatocytes, 10% in fibroblasts, 15% in amoebas and up to 50–80% in activated platelets. There are a number of different types of actin with slightly different structures and functions. This means that α-actin is found exclusively in muscle fibres, while types β and γ are found in other cells. In addition, as the latter types have a high turnover rate the majority of them are found outside permanent structures. This means that the microfilaments found in cells other than muscle cells are present in three forms: * Microfilament networks - Animal cells commonly have a cell cortex under the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane A biological membrane, biomembrane or cell membrane is a selectively permeable membra ...

cell membrane
that contains a large number of microfilaments, which precludes the presence of
organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, ...
s. This network is connected with numerous Receptor (biochemistry), receptor cells that signal transduction, relay signals to the outside of a cell. * Microfilament bundles - These extremely long microfilaments are located in networks and, in association with contractile proteins such as non-muscular
myosin Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...

myosin
, they are involved in the movement of substances at an intracellular level. * Periodic actin rings - A periodic structure constructed of evenly spaced actin rings is recently found to specifically exist in axons (not dendrites). In this structure, the actin rings, together with spectrin tetramers that link the neighboring actin rings, form a cohesive
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

cytoskeleton
that supports the axon membrane. The structure periodicity may also regulate the sodium ion channels in axons.


Yeasts

Actin's cytoskeleton is key to the processes of
endocytosis Endocytosis is a in which are brought into the cell. The material to be internalized is surrounded by an area of , which then buds off inside the cell to form a containing the ingested material. Endocytosis includes (cell drinking) and (cell ...

endocytosis
,
cytokinesis Cytokinesis () is the part of the cell division biological process, process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of Mitosis, nuclear di ...

cytokinesis
, determination of cell polarity and morphogenesis in
yeast Yeasts are eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular ...

yeast
s. In addition to relying on actin these processes involve 20 or 30 associated proteins, which all have a high degree of evolutionary conservation, along with many signalling molecules. Together these elements allow a spatially and temporally modulated assembly that defines a cell's response to both internal and external stimuli. Yeasts contain three main elements that are associated with actin: patches, cables, and rings that, despite not being present for long, are subject to a dynamic equilibrium due to continual polymerization and depolymerization. They possess a number of accessory proteins including ADF/cofilin, which has a molecular weight of 16kDa and is coded for by a single gene, called ''COF1''; Aip1, a cofilin cofactor that promotes the disassembly of microfilaments; Srv2/CAP, a process regulator related to adenylate cyclase proteins; a profilin with a molecular weight of approximately 14 kDa that is related/associated with actin monomers; and twinfilin, a 40 kDa protein involved in the organization of patches.


Plants

Plant genome studies have revealed the existence of protein isovariants within the actin family of genes. Within ''Arabidopsis thaliana'', a dicotyledon used as a model organism, there are ten types of actin, nine types of α-tubulins, six β-tubulins, six profilins, and dozens of myosins. This diversity is explained by the evolutionary necessity of possessing variants that slightly differ in their temporal and spatial expression. The majority of these proteins were jointly expressed in the Tissue (biology), tissue analysed. Actin networks are distributed throughout the cytoplasm of cells that have been cultivated ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applie ...

in vitro
''. There is a concentration of the network around the nucleus that is connected via spokes to the cellular cortex, this network is highly dynamic, with a continuous polymerization and depolymerization. Even though the majority of plant cells have a Plant cell wall, cell wall that defines their morphology and impedes their movement, their microfilaments can generate sufficient force to achieve a number of cellular activities, such as, the cytoplasmic currents generated by the microfilaments and myosin. Actin is also involved in the movement of organelles and in cellular morphogenesis, which involve
cell division Cell division is the process by which a parent cell (biology), cell divides into two or more daughter cells. Cell division usually occurs as part of a larger cell cycle. In eukaryotes, there are two distinct types of cell division; a vegetative ...

cell division
as well as the elongation and differentiation of the cell. The most notable proteins associated with the actin cytoskeleton in plants include:
villin Villin is a 92.5 kDa The dalton or unified atomic mass unit (symbols: Da or u) is a unit Unit may refer to: Arts and entertainment * UNIT, a fictional military organization in the science fiction television series ''Doctor Who'' * Unit of acti ...
, which belongs to the same family as gelsolin/severin and is able to cut microfilaments and bind actin monomers in the presence of calcium cations; fimbrin, which is able to recognize and unite actin monomers and which is involved in the formation of networks (by a different regulation process from that of animals and yeasts); formins, which are able to act as an F-actin polymerization nucleating agent;
myosin Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...

myosin
, a typical molecular motor that is specific to eukaryotes and which in ''Arabidopsis thaliana'' is coded for by 17 genes in two distinct classes; CHUP1, which can bind actin and is implicated in the spatial distribution of chloroplasts in the cell; KAM1/MUR3 that define the morphology of the Golgi apparatus as well as the composition of xyloglucans in the cell wall; NtWLIM1, which facilitates the emergence of actin cell structures; and ERD10, which is involved in the association of organelles within cell membrane, membranes and microfilaments and which seems to play a role that is involved in an organism's reaction to Stress (biology), stress.


Nuclear actin

Nuclear actin was first noticed and described in 1977 by Clark and Merriam. Authors describe a protein present in the nuclear fraction, obtained from ''Xenopus laevis'' oocytes, which shows the same features as skeletal muscle actin. Since that time there have been many scientific reports about the structure and functions of actin in the nucleus (for review see: Hofmann 2009.) The controlled level of actin in the nucleus, its interaction with actin-binding proteins (ABP) and the presence of different isoforms allows actin to play an important role in many important nuclear processes.


Transport of actin through the nuclear membrane

The actin sequence does not contain a nuclear localization signal. The small size of actin (about 43 kDa) allows it to enter the nucleus by passive diffusion. Actin however shuttles between cytoplasm and nucleus quite quickly, which indicates the existence of active transport. The import of actin into the nucleus (probably in a complex with cofilin) is facilitated by the import protein importin 9. Low level of actin in the nucleus seems to be very important, because actin has two nuclear export signals (NES) into its sequence. Microinjected actin is quickly removed from the nucleus to the cytoplasm. Actin is exported at least in two ways, through XPO1, exportin 1 (EXP1) and XPO6, exportin 6 (Exp6). Specific modifications, such as SUMOylation, allows for nuclear actin retention. It was demonstrated that a mutation preventing SUMOylation causes rapid export of beta actin from the nucleus. Based on the experimental results a general mechanism of nuclear actin transport can be proposed: * In the cytoplasm cofilin bind ADP-actin monomers. This complex is actively imported into the nucleus. * Higher concentration of ATP in the nucleus (compared to the cytoplasm) promote ADP to ATP exchange in the actin-cofilin complex. This weakens the strength of binding of these two proteins. * Cofilin-actin complex finally dissociate after cofilin phosphorylation by nuclear LIM kinase. * Actin is SUMOylated and in this form is retained inside the nucleus. * Actin can form complexes with profilin and leave the nucleus via exportin 6.


The organization of nuclear actin

Nuclear actin exists mainly as a monomer, but can also form dynamic oligomers and short polymers. Nuclear actin organization varies in different cell types. For example, in ''Xenopus'' oocytes (with higher nuclear actin level in comparison to somatic cells) actin forms filaments, which stabilize nucleus architecture. These filaments can be observed under the microscope thanks to fluorophore-conjugated phalloidin staining. In somatic cell nuclei, however, actin filaments cannot be observed using this technique. The DNase I inhibition assay, so far the only test which allows the quantification of the polymerized actin directly in biological samples, has revealed that endogenous nuclear actin indeed occurs mainly in a monomeric form. Precisely controlled level of actin in the cell nucleus, lower than in the cytoplasm, prevents the formation of filaments. The polymerization is also reduced by the limited access to actin monomers, which are bound in complexes with ABPs, mainly cofilin.


Actin isoforms in the cell nucleus

Little attention is paid to actin isoforms; however, it has been shown that different isoforms of actin are present in the cell nucleus. Actin isoforms, despite of their high sequence similarity, have different biochemical properties such as polymerization and depolymerization kinetic. They also show different localization and functions. The level of actin isoforms, both in the cytoplasm and the nucleus, may change for example in response to stimulation of cell growth or arrest of proliferation and transcriptional activity. Research concerns on nuclear actin are usually focused on isoform beta. However the use of antibodies directed against different actin isoforms allows identifying not only the cytoplasmic beta in the cell nucleus, but also: * gamma actin in the cell nuclei of human melanoma, * alpha skeletal muscle actin in the nuclei of mouse myoblasts, * cytoplasmic gamma actin and also alpha smooth muscle actin in the nucleus of the foetal mouse fibroblast The presence of different isoforms of actin may have a significant effect on its function in nuclear processes, especially because the level of individual isoforms can be controlled independently.


Nuclear actin functions

Functions of actin in the nucleus are associated with its ability to polymerize and interaction with variety of ABPs and with structural elements of the nucleus. Nuclear actin is involved in: * Architecture of the nucleus - Interaction of actin with alpha II-spectrin and other proteins are important for maintaining proper shape of the nucleus. * Transcription – Actin is involved in chromatin reorganization, transcription initiation and interaction with the transcription complex. Actin takes part in the regulation of chromatin structure, interacting with RNA polymerase I, II and III. In Pol I transcription, actin and myosin (MYO1C, which binds DNA) act as a molecular motor. For Pol II transcription, β-actin is needed for the formation of the preinitiation complex. Pol III contains β-actin as a subunit. Actin can also be a component of chromatin remodelling complexes as well as pre-mRNP particles (that is, precursor messenger RNA bundled in proteins), and is involved in nuclear pore, nuclear export of RNAs and proteins. * Regulation of gene activity – Actin binds to the regulatory regions of different kinds of genes. Actin's ability to regulate gene activity is used in the molecular reprogramming method, which allows differentiated cells return to their embryonic state. * Translocation of the activated chromosome fragment from under membrane region to euchromatin where transcription starts. This movement requires the interaction of actin and myosin. * Integration of different cellular compartments. Actin is a molecule that integrates cytoplasmic and nuclear signal transduction pathways. An example is the activation of transcription in response to serum stimulation of cells ''in vitro''. * Immune response - Nuclear actin polymerizes upon T-cell receptor stimulation and is required for cytokine expression and antibody production ''in vivo''. Due to its ability to undergo conformational changes and interaction with many proteins, actin acts as a regulator of formation and activity of protein complexes such as transcriptional complex.


Muscular contraction


Outline of a muscle contraction

In muscle cells, actomyosin myofibrils make up much of the cytoplasmic material. These myofibrils are made of ''thin filaments'' of actin (typically around 7 nm in diameter), and ''thick filaments'' of the motor-protein
myosin Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...

myosin
(typically around 15 nm in diameter). These myofibrils use energy derived from
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
to create movements of cells, such as muscle contraction. Using the hydrolysis of ATP for energy, myosin heads undergo a cycle during which they attach to thin filaments, exert a tension, and then, depending on the load, perform a power stroke that causes the thin filaments to slide past, shortening the muscle. In contractile bundles, the actin-bundling protein alpha-actinin separates each thin filament by ≈35 nm. This increase in distance allows thick filaments to fit in between and interact, enabling deformation or contraction. In deformation, one end of myosin is bound to the plasma membrane, while the other end "walks" toward the plus end of the actin filament. This pulls the membrane into a different shape relative to the cell cortex. For contraction, the myosin molecule is usually bound to two separate filaments and both ends simultaneously "walk" toward their filament's plus end, sliding the actin filaments closer to each other. This results in the shortening, or contraction, of the actin bundle (but not the filament). This mechanism is responsible for muscle contraction and
cytokinesis Cytokinesis () is the part of the cell division biological process, process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of Mitosis, nuclear di ...

cytokinesis
, the division of one cell into two.


Actin’s role in muscle contraction

The helical F-actin filament found in muscles also contains a
tropomyosin Tropomyosin is a two-stranded alpha-helical, coiled coil A coiled coil is a structural motif In a polymer, chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that ...

tropomyosin
molecule, a 40-
nanometre file:EM Spectrum Properties edit.svg, 330px, Different lengths as in respect to the Electromagnetic spectrum, measured by the Metre and its derived scales. The nanometre is often used to express dimensions on an atomic scale and mostly in the Mo ...
protein that is wrapped around the F-actin helix. During the resting phase the tropomyosin covers the actin's active sites so that the actin-myosin interaction cannot take place and produce muscular contraction (the interaction gives rise to a movement between the two proteins that, because it is repeated many times, produces a contraction). There are other protein molecules bound to the tropomyosin thread, these include the
troponin image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL Troponin, or ...
s that have three polymers:
troponin I Troponin I is a cardiac and skeletal muscle protein family. It is a part of the troponin protein complex, where it binds to actin in thin myofilaments to hold the actin-tropomyosin complex in place. Troponin I prevents myosin from binding to actin ...
,
troponin T Troponin T (shortened TnT or TropT) is a part of the troponin image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = trop ...
, and
troponin C Troponin C is a protein which is part of the troponin image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; ma ...
. Tropomyosin's regulatory function depends on its interaction with troponin in the presence of Ca2+ ions. Both actin and
myosin Myosins () are a superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilie ...

myosin
are involved in
muscle Skeletal muscles (commonly referred to as muscles) are organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's tissues can be broadly cat ...

muscle
contraction and relaxation and they make up 90% of muscle protein. The overall process is initiated by an external signal, typically through an action potential stimulating the muscle, which contains specialized cells whose interiors are rich in actin and myosin filaments. The contraction-relaxation cycle comprises the following steps: # Depolarization of the sarcolemma and transmission of an action potential through the T-tubules. # Opening of the sarcoplasmic reticulum’s calcium, Ca2+ channels. # Increase in cytosolic Ca2+ concentrations and the interaction of these cations with troponin causing a conformational change in its
structure A structure is an arrangement and organization of interrelated elements in a material object or system A system is a group of Interaction, interacting or interrelated elements that act according to a set of rules to form a unified whole. ...

structure
. This in turn alters the structure of tropomyosin, which covers actin's active site, allowing the formation of myosin-actin cross-links (the latter being present as thin filaments). # Movement of myosin heads over the thin filaments, this can either involve ATP or be independent of ATP. The former mechanism, mediated by
ATPase ATPases (, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, adenosine 5'-triphosphatase, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
activity in the myosin heads, causes the movement of the actin filaments towards the Sarcomere, Z-disc. # Ca2+ capture by the sarcoplasmic reticulum, causing a new conformational change in tropomyosin that inhibits the actin-myosin interaction.


Other biological processes

The traditional image of actin's function relates it to the maintenance of the cytoskeleton and, therefore, the organization and movement of organelles, as well as the determination of a cell's shape. However, actin has a wider role in eukaryotic cell physiology, in addition to similar functions in
prokaryote A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual conti ...
s. * Cytokinesis. Cell division in animal cells and yeasts normally involves the separation of the parent cell into two daughter cells through the constriction of the central circumference. This process involves a constricting ring composed of actin, myosin, and actinin, α-actinin. In the fission yeast ''Schizosaccharomyces pombe'', actin is actively formed in the constricting ring with the participation of Arp2/3, Arp3, the formin Cdc12, profilin, and WASp, along with preformed microfilaments. Once the ring has been constructed the structure is maintained by a continual assembly and disassembly that, aided by the Arp2/3 complex and formins, is key to one of the central processes of cytokinesis. The totality of the contractile ring, the spindle apparatus, microtubules, and the dense peripheral material is called the "Fleming body" or "intermediate body". * Apoptosis. During programmed cell death the ICE/ced-3 family of proteases (one of the interleukin-1β-converter proteases) degrade actin into two fragments ''in vivo''; one of the fragments is 15 kDa and the other 31 kDa. This represents one of the mechanisms involved in destroying cell viability that form the basis of apoptosis. The protease calpain has also been shown to be involved in this type of cell destruction; just as the use of calpain inhibitors has been shown to decrease actin proteolysis and the degradation of
DNA Deoxyribonucleic acid (; DNA) is a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical ...

DNA
(another of the characteristic elements of apoptosis). On the other hand, the Stress (biology), stress-induced triggering of apoptosis causes the reorganization of the actin cytoskeleton (which also involves its polymerization), giving rise to structures called stress fibers; this is activated by the MAPK/ERK pathway, MAP kinase pathway. * Cellular adhesion and Developmental biology, development. The adhesion between cells is a characteristic of multicellular organisms that enables Tissue (biology), tissue specialization and therefore increases cell complexity. Adhesion of cell epithelium, epithelia involves the actin cytoskeleton in each of the joined cells as well as cadherins acting as extracellular elements with the connection between the two mediated by catenins. Interfering in actin dynamics has repercussions for an organism's development, in fact actin is such a crucial element that systems of redundant
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
s are available. For example, if the α-actinin or gelation factor gene has been removed in ''Dictyostelium'' individuals do not show an anomalous phenotype possibly due to the fact that each of the proteins can perform the function of the other. However, the development of Mutation, double mutations that lack both gene types is affected. * Gene expression modulation. Actin's state of polymerization affects the pattern of
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...

gene expression
. In 1997, it was discovered that cytocalasin D-mediated depolymerization in Schwann cells causes a specific pattern of expression for the genes involved in the myelinization of this type of Neuron, nerve cell. F-actin has been shown to modify the transcriptome in some of the life stages of unicellular organisms, such as the fungus ''Candida albicans''. In addition, proteins that are similar to actin play a regulatory role during spermatogenesis in Muridae, mice and, in yeasts, actin-like proteins are thought to play a role in the regulation of Epigenetics, gene expression. In fact, actin is capable of acting as a transcription initiator when it reacts with a type of nuclear myosin that interacts with RNA polymerases and other enzymes involved in the transcription process. * Stereocilia dynamics. Some cells develop fine filliform outgrowths on their surface that have a Somatosensory system, mechanosensory function. For example, this type of organelle is present in the Organ of Corti, which is located in the ear. The main characteristic of these structures is that their length can be modified. The molecular architecture of the stereocilia includes a paracrystalline actin core in dynamic equilibrium with the monomers present in the adjacent cytosol. Type VI and VIIa myosins are present throughout this core, while myosin XVa is present in its extremities in quantities that are proportional to the length of the stereocilia. * Intrinsic chirality. Actomyosin networks have been implicated in generating an intrinsic chirality in individual cells. Cells grown out on chiral surfaces can show a directional left/right bias that is actomyosin dependent.


Molecular pathology

The majority of mammals possess six different actin
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
s. Of these, two code for the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

cytoskeleton
(''ACTB'' and ''ACTG1'') while the other four are involved in skeletal striated muscle (''ACTA1''), smooth muscle tissue (''ACTA2''), Intestine, intestinal muscles (''ACTG2'') and cardiac muscle (''ACTC1''). The actin in the cytoskeleton is involved in the Pathogenesis, pathogenic mechanisms of many Pathogen, infectious agents, including HIV. The vast majority of the
mutation In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...
s that affect actin are point mutations that have a Dominance (genetics), dominant effect, with the exception of six mutations involved in nemaline myopathy. This is because in many cases the mutant of the actin monomer acts as a “cap” by preventing the elongation of F-actin.


Pathology associated with ''ACTA1''

''ACTA1'' is the gene that codes for the α-
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallo ...
of actin that is predominant in human skeletal striated muscles, although it is also expressed in heart muscle and in the Thyroid, thyroid gland. Its DNA sequence consists of seven exons that produce five known Transcription (genetics), transcripts. The majority of these consist of point mutations causing substitution of
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s. The mutations are in many cases associated with a phenotype that determines the severity and the course of the affliction. The mutation alters the structure and function of skeletal muscles producing one of three forms of myopathy: type 3 nemaline myopathy, Congenital myopathy, congenital myopathy with an excess of thin myofilaments (CM) and Congenital myopathy#Congenital fiber type disproportion, congenital myopathy with fibre type disproportion (CMFTD). Mutations have also been found that produce Central core disease, core myopathies. Although their phenotypes are similar, in addition to typical nemaline myopathy some specialists distinguish another type of myopathy called actinic nemaline myopathy. In the former, clumps of actin form instead of the typical rods. It is important to state that a patient can show more than one of these phenotypes in a biopsy. The most common symptoms consist of a typical facial morphology (myopathic Facies (medical), facies), muscular weakness, a delay in motor development and respiratory difficulties. The course of the illness, its gravity, and the age at which it appears are all variable and overlapping forms of myopathy are also found. A symptom of nemaline myopathy is that "nemaline rods" appear in differing places in type 1 muscle fibres. These rods are non-pathognomonic structures that have a similar composition to the Z disks found in the sarcomere. The pathogenesis of this myopathy is very varied. Many mutations occur in the region of actin's indentation near to its
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
binding sites, while others occur in Domain 2, or in the areas where interaction occurs with associated proteins. This goes some way to explain the great variety of clumps that form in these cases, such as Nemaline or Intranuclear Bodies or Zebra Bodies. Changes in actin's Protein folding, folding occur in nemaline myopathy as well as changes in its aggregation and there are also changes in the Gene expression, expression of other associated proteins. In some variants where intranuclear bodies are found the changes in the folding masks the Nuclear pore#Export of proteins, nucleus's protein exportation signal so that the accumulation of actin's mutated form occurs in the cell nucleus. On the other hand, it appears that mutations to ''ACTA1'' that give rise to a CFTDM have a greater effect on sarcomeric function than on its structure. Recent investigations have tried to understand this apparent paradox, which suggests there is no clear correlation between the number of rods and muscular weakness. It appears that some mutations are able to induce a greater apoptosis rate in type II muscular fibres.


In smooth muscle

There are two isoforms that code for actins in the smooth muscle tissue: ''ACTG2'' codes for the largest actin isoform, which has nine exons, one of which, the one located at the 5' end, is not Translation (biology), translated. It is a γ-actin that is expressed in the enteric smooth muscle. No mutations to this gene have been found that correspond to pathologies, although DNA microarray, microarrays have shown that this protein is more often expressed in cases that are resistant to chemotherapy using cisplatin. ''ACTA2'' codes for an α-actin located in the smooth muscle, and also in vascular smooth muscle. It has been noted that the MYH11 mutation could be responsible for at least 14% of hereditary Aortic aneurism, thoracic aortic aneurisms particularly Type 6. This is because the mutated variant produces an incorrect filamentary assembly and a reduced capacity for vascular smooth muscle contraction. Degradation of the Aorta, aortic media has been recorded in these individuals, with areas of disorganization and hyperplasia as well as stenosis of the aorta's vasa vasorum. The number of afflictions that the gene is implicated in is increasing. It has been related to Moyamoya disease and it seems likely that certain mutations in heterozygosis could confer a predisposition to many vascular pathologies, such as thoracic aortic aneurysm and ischaemic heart disease. The α-actin found in smooth muscles is also an interesting marker for evaluating the progress of liver cirrhosis.


In heart muscle

The ''ACTC1'' gene codes for the α-actin isoform present in heart muscle. It was first sequenced by Hamada and co-workers in 1982, when it was found that it is interrupted by five introns. It was the first of the six genes where alleles were found that were implicated in pathological processes. A number of structural disorders associated with point mutations of this gene have been described that cause malfunctioning of the heart, such as Type 1R dilated cardiomyopathy and Type 11 hypertrophic cardiomyopathy. Certain defects of the Atrium (heart), atrial septum have been described recently that could also be related to these mutations. Two cases of dilated cardiomyopathy have been studied involving a substitution of highly conserved
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s belonging to the protein domains that bind and intersperse with the sarcomere, Z discs. This has led to the theory that the dilation is produced by a defect in the transmission of muscle contraction, contractile force in the myocytes. The mutations in ACTC1 are responsible for at least 5% of hypertrophic cardiomyopathies. The existence of a number of point mutations have also been found: * Mutation E101K: changes of net charge and formation of a weak electrostatic link in the actomyosin-binding site. * P166A: interaction zone between actin monomers. * A333P: actin-myosin interaction zone. Pathogenesis appears to involve a compensatory mechanism: the mutated proteins act like toxins with a dominant effect, decreasing the heart's ability to Heart#Functioning, contract causing abnormal mechanical behaviour such that the hypertrophy, that is usually delayed, is a consequence of the cardiac muscle's normal response to stress (physiology), stress. Recent studies have discovered ACTC1 mutations that are implicated in two other pathological processes: Infantile idiopathic restrictive cardiomyopathy, and Noncompaction cardiomyopathy, noncompaction of the left ventricular myocardium.


In cytoplasmatic actins

''ACTB'' is a highly complex Locus (genetics), locus. A number of
pseudogene Pseudogenes are nonfunctional segments of DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon ...
s exist that are distributed throughout the genome, and its sequence contains six exons that can give rise to up to 21 different transcriptions by alternative splicing, which are known as the β-actins. Consistent with this complexity, its products are also found in a number of locations and they form part of a wide variety of processes (
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

cytoskeleton
, NuA4 histone-acyltransferase complex, cell nucleus) and in addition they are associated with the mechanisms of a great number of pathological processes (Cancer, carcinomas, juvenile dystonia, infection mechanisms, nervous system malformations and tumour invasion, among others). A new form of actin has been discovered, kappa actin, which appears to substitute for β-actin in processes relating to tumours. Three pathological processes have so far been discovered that are caused by a direct alteration in gene sequence: * Hemangiopericytoma with t(7;12)(p22;q13)-translocations is a rare affliction, in which a Mutation#By effect on structure, translocational mutation causes the fusion of the ''ACTB'' gene over GLI1 in Chromosome 12 (human), Chromosome 12. * Juvenile onset dystonia is a rare degenerative disease that affects the central nervous system; in particular, it affects areas of the neocortex and thalamus, where rod-like eosinophilic inclusions are formed. The affected individuals represent a phenotype with deformities on the median line, sensory Deafness, hearing loss and dystonia. It is caused by a point mutation in which the amino acid tryptophan replaces arginine in position 183. This alters actin's interaction with the ADF/
cofilin ADF/cofilin is a family of actin-binding proteinActin-binding proteins (also known as ABPs) are proteins that bind to actin Actin is a family In human society, family (from la, familia) is a group of people related either by consangui ...
system, which regulates the dynamics of Neuron, nerve cell cytoskeleton formation. * A dominant point mutation has also been discovered that causes neutrophil granulocyte dysfunction and recurring
infection An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host A host is a person responsible for guests at an event or for providing hospitality during it. Host may ...

infection
s. It appears that the mutation modifies the domain responsible for binding between profilin and other regulatory proteins. Actin's affinity for profilin is greatly reduced in this allele. The ''ACTG1'' locus codes for the cytosolic γ-actin protein that is responsible for the formation of cytoskeletal
microfilament Actin cytoskeleton of mouse embryo fibroblasts, stained with Fluorescein isothiocyanate-phalloidin, 250px Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cell (biology), cells that form part of the ...
s. It contains six exons, giving rise to 22 different Messenger RNA, mRNAs, which produce four complete
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallo ...
s whose form of expression is probably dependent on the type of Tissue (biology), tissue they are found in. It also has two different Promoter (genetics), DNA promoters. It has been noted that the sequences translated from this locus and from that of β-actin are very similar to the predicted ones, suggesting a common ancestral sequence that suffered duplication and genetic conversion. In terms of pathology, it has been associated with processes such as amyloidosis, retinitis pigmentosa, infection mechanisms, kidney diseases, and various types of congenital hearing loss. Six autosomal-dominant point mutations in the sequence have been found to cause various types of hearing loss, particularly sensorineural hearing loss linked to the DFNA 20/26 locus. It seems that they affect the stereocilia of the ciliated cells present in the inner ear's Organ of Corti. β-actin is the most abundant protein found in human tissue, but it is not very abundant in ciliated cells, which explains the location of the pathology. On the other hand, it appears that the majority of these mutations affect the areas involved in linking with other proteins, particularly actomyosin. Some experiments have suggested that the pathological mechanism for this type of hearing loss relates to the F-actin in the mutations being more sensitive to cofilin than normal. However, although there is no record of any case, it is known that γ-actin is also expressed in skeletal muscles, and although it is present in small quantities, model organisms have shown that its absence can give rise to myopathies.


Other pathological mechanisms

Some infectious agents use actin, especially cytoplasmic actin, in their Alternation of generations, life cycle. Two basic forms are present in
bacteria Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typ ...

bacteria
: * ''Listeria monocytogenes'', some species of ''Rickettsia'', ''Shigella flexneri'' and other intracellular germs escape from phagocytosis, phagocytic vacuoles by coating themselves with a capsule of actin filaments. ''L. monocytogenes'' and ''S. flexneri'' both generate a tail in the form of a "comet tail" that gives them mobility. Each species exhibits small differences in the molecular polymerization mechanism of their "comet tails". Different displacement velocities have been observed, for example, with ''Listeria'' and ''Shigella'' found to be the fastest. Many experiments have demonstrated this mechanism ''in vitro''. This indicates that the bacteria are not using a myosin-like protein motor, and it appears that their propulsion is acquired from the pressure exerted by the polymerization that takes place near to the microorganism's cell wall. The bacteria have previously been surrounded by ABPs from the host, and as a minimum the covering contains
Arp2/3 complex Arp2/3 complex (Actin Related Protein 2/3 complex) is a seven-subunit protein complex that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the microfilament, actin cytoskeleton and is found in most actin ...
, Ena/Vasp homology proteins, Ena/VASP proteins, cofilin, a buffering protein and nucleation promoters, such as vinculin complex. Through these movements they form protrusions that reach the neighbouring cells, infecting them as well so that the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
can only fight the infection through cell immunity. The movement could be caused by the modification of the curve and debranching of the filaments. Other species, such as ''Mycobacterium marinum'' and ''Burkholderia pseudomallei'', are also capable of localized polymerization of cellular actin to aid their movement through a mechanism that is centered on the Arp2/3 complex. In addition the vaccine
virus A virus is a submicroscopic infectious agent In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecu ...

virus
''Vaccinia'' also uses elements of the actin cytoskeleton for its dissemination. * ''Pseudomonas aeruginosa'' is able to form a protective biofilm in order to escape a host (biology), host organism’s defences, especially Neutrophil granulocyte, white blood cells and Antibacterial, antibiotics. The biofilm is constructed using
DNA Deoxyribonucleic acid (; DNA) is a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical ...

DNA
and actin filaments from the host organism. In addition to the previously cited example, actin polymerization is stimulated in the initial steps of the internalization of some viruses, notably HIV, by, for example, inactivating the cofilin complex. The role that actin plays in the invasion process of cancer cells has still not been determined.


Evolution

The eukaryotic cytoskeleton of organisms among all Phylogenetic, taxonomic groups have similar components to actin and tubulin. For example, the protein that is coded by the ''ACTG2'' gene in humans is completely equivalent to the Homology (biology), homologues present in rats and mice, even though at a
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
level the similarity decreases to 92%. However, there are major differences with the equivalents in prokaryotes (FtsZ and
MreB MreB is a protein found in bacteria that has been identified as a homologue of actin Actin is a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity ...

MreB
), where the similarity between nucleotide sequences is between 40−50 % among different
bacteria Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typ ...

bacteria
and
archaea Archaea ( ; singular archaeon ) constitute a domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a pa ...

archaea
species. Some authors suggest that the ancestral protein that gave rise to the model eukaryotic actin resembles the proteins present in modern bacterial cytoskeletons. Some authors point out that the behaviour of actin, tubulin, and histone, a protein involved in the stabilization and regulation of DNA, are similar in their ability to bind nucleotides and in their ability of take advantage of Brownian motion. It has also been suggested that they all have a common ancestor. Therefore,
evolution Evolution is change in the heritable Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, ...

evolution
ary processes resulted in the diversification of ancestral proteins into the varieties present today, conserving, among others, actins as efficient molecules that were able to tackle essential ancestral biological processes, such as
endocytosis Endocytosis is a in which are brought into the cell. The material to be internalized is surrounded by an area of , which then buds off inside the cell to form a containing the ingested material. Endocytosis includes (cell drinking) and (cell ...

endocytosis
.


Equivalents in bacteria

The Cytoskeleton#Prokaryotic cytoskeleton, bacterial cytoskeleton may not be as complex as that found in
eukaryote Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryote
s; however, it contains proteins that are highly similar to actin monomers and polymers. The bacterial protein
MreB MreB is a protein found in bacteria that has been identified as a homologue of actin Actin is a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity ...

MreB
polymerizes into thin non-helical filaments and occasionally into helical structures similar to F-actin. Furthermore, its crystalline structure is very similar to that of G-actin (in terms of its three-dimensional conformation), there are even similarities between the MreB protofilaments and F-actin. The bacterial cytoskeleton also contains the FtsZ proteins, which are similar to
tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular protein 300px, 3-dimensional structure of hemoglobin, a globular protein. Globular proteins or spheroproteins are spherical ("globe-like") protein ...

tubulin
. Bacteria therefore possess a cytoskeleton with homologous elements to actin (for example, MreB, AlfA, ParM, FtsA, and MamK), even though the amino acid sequence of these proteins diverges from that present in animal cells. However, such proteins have a high degree of protein structure, structural similarity to eukaryotic actin. The highly dynamic microfilaments formed by the aggregation of MreB and ParM are essential to cell viability and they are involved in cell morphogenesis, chromosome segregation, and cell polarity. ParM is an actin homologue that is coded in a
plasmid A plasmid is a small, extrachromosomal DNA Extrachromosomal DNA (abbreviated ecDNA) is any DNA that is found off the chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. Most eukaryo ...
and it is involved in the regulation of plasmid DNA. ParMs from different bacterial plasmids can form astonishingly diverse helical structures comprising two or four strands to maintain faithful plasmid inheritance.


Applications

Actin is used in scientific and technological laboratories as a track for molecular motors such as myosin (either in muscle tissue or outside it) and as a necessary component for cellular functioning. It can also be used as a diagnostic tool, as several of its anomalous variants are related to the appearance of specific pathologies. *Nanotechnology. Actin-myosin systems act as molecular motors that permit the transport of vesicles and organelles throughout the cytoplasm. It is possible that actin could be applied to nanotechnology as its dynamic ability has been harnessed in a number of experiments including those carried out in acellular systems. The underlying idea is to use the microfilaments as tracks to guide molecular motors that can transport a given load. That is actin could be used to define a circuit along which a load can be transported in a more or less controlled and directed manner. In terms of general applications, it could be used for the directed transport of molecules for deposit in determined locations, which would permit the controlled assembly of nanostructures. These attributes could be applied to laboratory processes such as on ''lab-on-a-chip'', in nanocomponent mechanics and in nanotransformers that convert mechanical energy into electrical energy. *Actin is used as an internal control in western blots to ascertain that equal amounts of protein have been loaded on each lane of the gel. In the blot example shown on the left side, 75 µg of total protein was loaded in each well. The blot was reacted with anti-β-actin antibody (for other details of the blot see the reference ) The use of actin as an internal control is based on the assumption that its expression is practically constant and independent of experimental conditions. By comparing the expression of the gene of interest to that of the actin, it is possible to obtain a relative quantity that can be compared between different experiments, whenever the expression of the latter is constant. It is worth pointing out that actin does not always have the desired stability in its
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...

gene expression
. *Health. Some
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is one of two, or more, forms of a given gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance ...
s of actin cause diseases; for this reason techniques for their detection have been developed. In addition, actin can be used as an indirect marker in surgical pathology: it is possible to use variations in the pattern of its distribution in tissue as a marker of invasion in neoplasm, neoplasia, vasculitis, and other conditions. Further, due to actin's close association with the apparatus of muscular contraction its levels in skeletal muscle diminishes when these tissues atrophy, it can therefore be used as a marker of this physiological process. *Food technology. It is possible to determine the quality of certain processed foods, such as embutido, sausages, by quantifying the amount of actin present in the constituent meat. Traditionally, a method has been used that is based on the detection of histidine, 3-methylhistidine in
hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile In chemistry, a nucleop ...

hydrolyzed
samples of these products, as this compound is present in actin and F-myosin's heavy chain (both are major components of muscle). The generation of this compound in flesh derives from the methylation of histidine residues present in both proteins.


Genes

Human genes encoding actin proteins include: * ACTA1 — alpha actin 1, skeletal muscle * ACTA2 — alpha actin 2, smooth muscle, aorta * ACTB — beta actin * ACTC1 — actin, alpha, cardiac muscle 1 * ACTG1 — gamma actin 1 * ACTG2 — gamma actin 2, smooth muscle, enteric


See also

* Actin remodeling — effect on cell structure and shape * Actin-binding protein * Active matter * Arp2/3 * Filopodia * FtsZ * Intermediate filament * Lamellipodium * Motor protein — converts chemical energy into mechanical work *
MreB MreB is a protein found in bacteria that has been identified as a homologue of actin Actin is a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity ...

MreB
 — one of the actin homologues in bacteria *Neuron * Phallotoxin


References


External links


Actin Staining Techniques (Live and Fixed Cell Staining)
* * *
3D macromolecular structures of actin filaments from the EM Data Bank(EMDB)
{{Autoantigens Cytoskeleton Structural proteins Autoantigens Articles containing video clips