Heat shock protein 27 (Hsp27) also known as heat shock protein beta-1 (HSPB1) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''HSPB1''
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 ...
.
Hsp27 is a
chaperone of the
sHsp
The heat shock protein Hsp20 family, also known as small heat shock proteins (sHSPs), is a family of heat shock proteins.
Prokaryotic and eukaryotic organisms respond to heat shock or other environmental stress by inducing the synthesis of pr ...
(small
heat shock protein
Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including ex ...
) group among α-
crystallin
In anatomy, a crystallin is a water-soluble structural protein found in the lens and the cornea of the eye accounting for the transparency of the structure. It has also been identified in other places such as the heart, and in aggressive breast ...
,
Hsp20
The heat shock protein Hsp20 family, also known as small heat shock proteins (sHSPs), is a family of heat shock proteins.
Prokaryotic and eukaryotic organisms respond to heat shock or other environmental stress by inducing the synthesis of prot ...
, and others. The common functions of sHsps are chaperone activity, thermotolerance, inhibition of
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, regulation of cell development, and
cell differentiation
Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
. They also take part in
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
.
Structure
sHsps have some structural features in common: Very characteristic is a homologous and highly conserved amino acid sequence, the so-called α-crystallin domain near the
C-terminus
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
Proteins are large biomolecules and macromolecules that comp ...
. These domains consist of 80 to 100 residues with sequence homology between 20% and 60% and fold into
β-sheets, which are important for the formation of stable dimers.
Hsp27 is rather unique among sHsps in that its α-crystallin domain contains a
cysteine
Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
residue at its dimer interface, which can become oxidized to form a
disulfide
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 inorg ...
bond that covalently links the dimer.
The
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 or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
consists of a less conserved region, the so-called WD/EPF domain, followed by a short variable sequence with a rather conservative site near the end of this domain. The C-terminal region of sHsps consists of the above mentioned α-crystallin domain, followed by a variable sequence with high motility and flexibility.
Despite relatively low levels of global sequence conservation in the C-terminal region, many sHsps contain a locally conserved Ile-Xxx-Ile/Val (IxI/V) motif that plays a role in regulating the assembly of
oligomers
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
.
It is highly flexible and polar because of its negative charges.
Probably it functions as a mediator of solubility for hydrophobic sHsps and it stabilizes the protein and protein/substrate complexes. This was shown by elimination of the C-terminal tail in Hsp27Δ182-205
and in Hsp25Δ18.
In the case of Hsp27, the IxI/V motif corresponds to 181-Ile-Pro-Val-183, and this region of the protein plays a critical role, as the mutation of the central Pro residue causes the hereditary motor neuropathy
Charcot-Marie-Tooth disease.
Oligomerization
Hsp27 forms large, dynamic oligomers with an average mass near 500 kDa ''in vitro''.
The N-terminus of Hsp27, with its WD/EPF-region, is essential for the development of these large
oligomers
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
.
Hsp27-oligomers consist of stable
dimers, which are formed by two α-crystallin-domains of neighboring
monomers
A monomer ( ; ''wikt:mono-, mono-'', "one" + ''wikt:-mer, -mer'', "part") is a molecule that can chemical reaction, react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called ...
,
which was first shown in crystal structures of the proteins MjHSP16.5 from ''
Methanocaldococcus jannaschii
''Methanocaldococcus jannaschii'' (formerly ''Methanococcus jannaschii'') is a thermophile, thermophilic methanogenic archaean in the class Methanococci. It was the first archaeon, and third organism, to have its complete genome genome sequencing ...
''
and wheat Hsp16.9.
Therefore the first step in the oligomeric process involves dimerization of the α-crystallin domain. In
metazoans, dimerization by α-crystallin domains proceeds through the formation of a long β-strand at the interface. The amino acid sequences in this region, however, are predicted to be disordered
Indeed, the α-crystallin domain of Hsp27 partially unfolds in its monomeric state and is less stable than the dimer.
The oligomerization of Hsp27 is a dynamic process: There is a balance between stable dimers and oligomers (up to 800
kDa
The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...
) consisting of 16 to 32 subunits and a high exchange rate of subunits.
The oligomerization depends on the physiology of the cells, the
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
status of Hsp27 and the exposure to stress. Stress induces an increase of
expression (after hours) and phosphorylation (after several minutes) of Hsp27. Stimulation of the p38
MAP kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammato ...
cascade by differentiating agents,
mitogens
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen.
The cell cycle
Mitogens ac ...
,
inflammatory cytokines
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
such as
TNFα
Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
and
IL-1β
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
,
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
and other
oxidants
An oxidizing agent (also known as an oxidant, oxidizer, electron recipient, or electron acceptor) is a substance in a redox chemical reaction that gains or " accepts"/"receives" an electron from a (called the , , or ''electron donor''). In ot ...
,
leads to the activation of MAPKAP kinases 2 and 3 which directly phosphorylate mammalian sHsps.
The phosphorylation plays an important role for the formation of oligomers in exponentially growing cells ''in vitro'', but the oligomerization in
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
cells growing ''in vivo'' or growing at confluence ''in vitro'' is dependent on cell-cell contact, but not on the phosphorylation status.
Furthermore, it was shown that HSP27 contains an Argpyrimidine modification.
In all probability, the oligomerization status is connected with the chaperone activity: aggregates of large oligomers have high chaperone activity, whereas dimers and monomers have relatively higher chaperone activity.
Cellular localization
Hsp27 appears in many
cell type
A cell type is a classification used to identify cells that share morphological or phenotypical features. A multicellular organism may contain cells of a number of widely differing and specialized cell types, such as muscle cells and skin cell ...
s, especially all types of
muscle
Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
cells. It is located mainly in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
, but also in the perinuclear region,
endoplasmatic reticulum
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for "little ne ...
, and
nucleus
Nucleus (: nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucleu ...
. It is overexpressed during different stages of cell differentiation and development. This suggests an essential role for Hsp27 in the differentiation of tissues.
An affinity of high expression levels of different phosphorylated Hsp27 species and
muscle
Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
/
neurodegenerative diseases
A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
and various
cancers
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
was observed.
High expression levels possibly are in inverse relation with
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...
,
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
, and resistance to
chemotherapy
Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
.
High levels of Hsp27 were also found in sera of
breast cancer
Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
patients;
therefore Hsp27 could be a potential diagnostic marker.
Function
The main function of Hsp27 is to provide thermotolerance ''in vivo'', cytoprotection, and support of cell survival under stress conditions. More specialized functions of Hsp27 are manifold and complex. ''In vitro'' it acts as an
ATP-independent chaperone by inhibiting protein aggregation and by stabilizing partially denatured proteins, which ensures refolding by the
Hsp70
The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms and play crucial roles in the development of can ...
-complex. Hsp27 is also involved in the
apoptotic
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...
signalling pathway. Hsp27 interacts with the outer
mitochondrial
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
membranes and interferes with the activation of
cytochrome c/
Apaf-1/dATP complex and therefore inhibits the activation of
procaspase-9.
The phosphorylated form of Hsp27 inhibits
Daxx apoptotic protein and prevents the association of Daxx with Fas and Ask1.
Moreover, Hsp27 phosphorylation leads to the activation of TAK1 and TAK1-p38/ERK pro-survival signaling, thus opposing TNF-α-induced apoptosis.
A well documented function of Hsp27 is the interaction with
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
and intermediate filaments. It prevents the formation of non-covalent filament/filament interactions of the intermediate filaments and protects actin filaments from fragmentation. It also preserves the focal contacts fixed at 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 ...
.
Another function of Hsp27 is the activation of the
proteasome
Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
. It speeds up the degradation of irreversibly denatured proteins and junkproteins by binding to
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...
ated proteins and to the 26S proteasome. Hsp27 enhances the activation of the
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
pathway, that controls a lot of processes, such as cell growth and inflammatory and stress responses.
The cytoprotective properties of Hsp27 result from its ability to modulate
reactive oxygen species
In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
and to raise
glutathione
Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...
levels.
Probably Hsp27 – among other chaperones – is involved in the process of cell differentiation.
Changes of Hsp27 levels were observed in
Ehrlich ascite cells,
embryonic stem cell
Embryonic stem cells (ESCs) are Cell potency#Pluripotency, pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-Implantation (human embryo), implantation embryo. Human embryos reach the blastocyst stage 4� ...
s, normal
B-cells
B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
, B-
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
cells,
osteoblast
Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...
s,
keratinocyte
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
s,
neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s etc. The upregulation of Hsp27 correlates with the rate of phosphorylation and with an increase of large oligomers. It is possible that Hsp27 plays a crucial role in the termination of growth.
Clinical significance
Motor neuropathies
At least 12 disease-causing mutations in this gene have been discovered.
Heritable mutations in ''HSPB1'' cause
distal hereditary motor neuropathies and the motor neuropathy
Charcot-Marie-Tooth disease.
There are
missense
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn al ...
mutations throughout the amino acid sequence of Hsp27, and most disease-causing mutations present with adult-onset symptoms.
One of the more severe Hsp27 mutants is the Pro182Leu mutant, which manifests symptomatically in the first few years of life and was additionally demonstrated in a transgenic mouse model.
The genetic basis of these diseases is typically
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
, meaning that only one allele contains a mutation. Since the wild-type ''HSPB1'' gene is also expressed alongside the mutated allele, the diseased cells contain a mixed populations of wild-type and mutant Hsp27, and ''in vitro'' experiments have shown that the two proteins can form heter-
oligomers
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
.
Roles in apoptosis
Notably, phosphorylated Hsp27 increases human prostate cancer (PCa) cell invasion, enhances cell proliferation, and suppresses Fas-induced apoptosis in human PCa cells. Unphosphorylated Hsp27 has been shown to act as an actin capping protein, preventing actin reorganization and, consequently, cell adhesion and motility. OGX-427, which targets HSP27 through an antisense mechanism, is currently undergoing testing in clinical trials.
Roles in cancer
Protein kinase C-mediated HSPB1 phosphorylation protects against ferroptosis, an iron-dependent form of non-apoptotic cell death, by reducing iron-mediated production of lipid reactive oxygen species. These novel data support the development of Hsp-targeting strategies and, specifically, anti-HSP27 agents for the treatment of ferroptosis-mediated cancer.
Interactions
Hsp27 has been shown to
interact with:
*
ASK1
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kin ...
,
*
C2orf73,
*
CRYAA
Alpha-crystallin A chain is a protein that in humans is encoded by the ''CRYAA'' gene.
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens ...
,
[
* ]CRYAB
Alpha-crystallin B chain is a protein that in humans is encoded by the ''CRYAB'' gene. It is part of the small heat shock protein family and functions as molecular chaperone that primarily binds misfolded proteins to prevent protein aggregation, ...
,
* CRYBB2
Beta-crystallin B2 is a protein that in humans is encoded by the ''CRYBB2'' gene.
Function
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate e ...
,
* HNRPD,
* HSPB8
Heat shock protein beta-8 is a protein that in humans is encoded by the ''HSPB8'' 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 i ...
,
* MK2,
* TAK1, and
* TGFB1I1.
References
External links
GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2
*
{{Chaperones
Heat shock proteins