Three-finger proteins or three-finger protein domains (3FP or TFPD) are a

protein superfamily A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology (biology), homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if n ...

consisting of small, roughly 60-80

amino acid residue In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

s with a common

tertiary structure Protein tertiary structure is the three-dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains and the ...

: three

beta strand The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...

loops extended from a

hydrophobic core The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and to be excluded by water#Properties, water. The word hydrophobic literally means "water-fearing", and it describes the Segregation in m ...

stabilized by

disulfide bond In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inor ...

s. The family is named for the outstretched "fingers" of the three loops. Members of the family have no

enzymatic An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as produc ...

activity, but are capable of forming protein-protein interactions with high specificity and

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

. The founding members of the family, also the best characterized by structure, are the

three-finger toxin Three-finger toxins (abbreviated 3FTx) are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic prote ...

s found in

snake venom Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is usually injected by unique fangs during a Snakebite, bite, though ...

, which have a variety of

pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...

effects, most typically by disruption of

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...

signaling. The family is also represented in non-toxic proteins, which have a wide

taxonomic 280px, Generalized scheme of taxonomy Taxonomy is a practice and science concerned with classification or categorization. Typically, there are two parts to it: the development of an underlying scheme of classes (a taxonomy) and the allocation ...

distribution; 3FP domains occur in the

extracellular domain An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A notabl ...

s of some

cell-surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral me ...

s as well as in GPI-anchored and

secreted Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mech ...

globular protein In biochemistry, globular proteins or spheroproteins are spherical ("globe-like") proteins and are one of the common protein types (the others being fibrous, disordered and membrane proteins). Globular proteins are somewhat water-soluble (form ...

s, usually involved in signaling.

Three-finger toxins

The founding members of the 3FP family are the

s (3FTx) often found in

. 3FTx proteins are widely distributed in venomous snake families, but are particularly enriched in the

family Family (from ) is a Social group, group of people related either by consanguinity (by recognized birth) or Affinity (law), affinity (by marriage or other relationship). It forms the basis for social order. Ideally, families offer predictabili ...

Elapidae Elapidae (, commonly known as elapids , from , variant of "sea-fish") is a family of snakes characterized by their permanently erect fangs at the front of the mouth. Most elapids are venomous, with the exception of the genus '' Emydocephalus ...

, in which the relative proportion of 3FTx to other venom toxins can reach 95%. Many 3FTx proteins are

neurotoxin Neurotoxins are toxins that are destructive to nervous tissue, nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insult (medical), insultsSpencer 2000 that can adversely affect function ...

s, though the mechanism of toxicity varies significantly even among proteins of relatively high

sequence identity In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Align ...

; common protein targets include those involved in

signaling, such as the

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

s, and

acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...

. Another large subfamily of 3FTx proteins is the

cardiotoxin Cardiotoxicity is the occurrence of heart dysfunction as electric or muscle damage, resulting in heart toxicity. This can cause heart failure, arrhythmia, myocarditis, and cardiomyopathy in patients. Some effects are reversible, while in others, p ...

s (also known as cytotoxins or cytolysins); this group is directly

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...

most likely due to interactions with

phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

s and possibly other components of the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

Ly6/uPAR family

The Ly6/uPAR family broadly describes a

gene family A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions. One such family are the genes for human hemoglobin subunits; the ten genes are in two clusters on ...

containing three-finger

s that are not toxic and not venom components; these are often known as LU domains and can be found in the

s of

s and in either GPI-anchored or

s. The family is named for two representative groups of members, the small globular protein lymphocyte antigen 6 (LY6) family and the urokinase plasminogen activator receptor (uPAR). Other receptors with LU domains include members of the transforming growth factor beta receptor (TGF-beta) superfamily, such as the

activin type 2 receptor The activin type 2 receptors belong to a larger TGF-beta receptor family and modulate signals for transforming growth factor beta ligands. These receptors are involved in a host of physiology, physiological processes including, cell growth, growt ...

; and bone morphogenetic protein receptor, type IA. Other LU domain proteins are small globular proteins such as

CD59 antigen CD59 glycoprotein, also known as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is a protein that in humans is encoded by the ''CD59'' gene. It is an LU domain and belongs to the LY6/Urokinase recept ...

, LYNX1,

SLURP1 Secreted Ly-6/uPAR-related protein 1 is a protein that in humans is encoded by the ''SLURP1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides i ...

, and SLURP2. Many LU domain containing proteins are involved in

signaling and bind

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

receptors, notably linking their function to a common

mechanism Mechanism may refer to: *Mechanism (economics), a set of rules for a game designed to achieve a certain outcome **Mechanism design, the study of such mechanisms *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a ...

of 3FTx toxicity. Members of the Ly6/uPAR family are believed to be the evolutionary ancestors of 3FTx toxins. Other LU proteins, such as the

, have well-studied functions in regulation of the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

Gene structure

Snake three-finger toxins and the Ly6/uPAR family members share a common

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

structure, typically consisting of two

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...

s and three

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s. The sequence of the first exon is generally well conserved compared to the other two. The third exon contains the major differentiating features between the two groups, as this is where the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

GPI-anchor

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

common among the Ly6/uPAR globular proteins is encoded.

Evolution and taxonomic distribution

Proteins of the general three-finger fold are widely distributed among

metazoan Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia (). With few exceptions, animals consume organic material, breathe oxygen, have myocytes and are able to move, can reproduce sexually, and grow from a ho ...

s. A 2008

bioinformatics Bioinformatics () is an interdisciplinary field of science that develops methods and Bioinformatics software, software tools for understanding biological data, especially when the data sets are large and complex. Bioinformatics uses biology, ...

study identified about 45 examples of such proteins, containing up to three three-finger domains, represented in the

human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual Mitochondrial DNA, mitochondria. These ar ...

. A more recent profile of the Ly6/uPAR

identified 35 human and at least 61

mouse A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...

family members in the organisms' respective genomes. The three-finger protein family is thought to have expanded through

gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene ...

in the

snake Snakes are elongated limbless reptiles of the suborder Serpentes (). Cladistically squamates, snakes are ectothermic, amniote vertebrates covered in overlapping scales much like other members of the group. Many species of snakes have s ...

lineage. 3FTx toxins are considered restricted to the

Caenophidia The Caenophidia are a derived clade of alethinophidian snakes, which contains over 80% of all the extant species of snakes. The largest family is Colubridae, but it also includes at least seven other families, at least four of which were once cl ...

, the taxon containing all venomous snakes; however at least one

homolog In biology, homology is similarity in anatomical structures or genes between organisms of different taxa due to shared ancestry, ''regardless'' of current functional differences. Evolutionary biology explains homologous structures as retained her ...

has been identified in the

Burmese python The Burmese python (''Python bivittatus'') is one of the largest species of snakes. It is native to a large area of Southeast Asia and is listed as Vulnerable on the IUCN Red List. Until 2009, it was considered a subspecies of the Indian pyth ...

, a closely related subgroup. Traditionally, 3FTx genes have been thought to have evolved by repeated events of duplication followed by neofunctionalization and recruitment to

gene expression Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

patterns restricted to venom glands. However, it has been argued that this process should be extremely rare and that

subfunctionalization Subfunctionalization was proposed by Stoltzfus (1999) and Force et al. (1999) as one of the possible outcomes of functional divergence that occurs after a gene duplication event, in which pairs of genes that originate from duplication, or paralogs ...

better explains the observed distribution. More recently, non-toxic 3FP proteins have been found to be widely expressed in many different tissues in snakes, prompting the

alternative hypothesis In statistical hypothesis testing, the alternative hypothesis is one of the proposed propositions in the hypothesis test. In general the goal of hypothesis test is to demonstrate that in the given condition, there is sufficient evidence supporting ...

that proteins of restricted expression in

saliva Saliva (commonly referred as spit or drool) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which ...

were selectively recruited for toxic functionality.

References

{{reflist, 32em

External links

* SCOP
SSF57302
* CATH
2.10.60.10
Protein folds Protein families