Hsp27
Encyclopedia
Heat shock protein 27 also known as heat shock protein beta-1 (HSPB1) is a protein
that in humans is encoded by the HSPB1 gene
.
Hsp27 is a chaperone of the sHsp (small heat shock protein
) group among ubiquitin
, α-crystallin
, Hsp20
and others. The common functions of sHsps are chaperone activity, thermotolerance, inhibition of apoptosis
, regulation of cell development, and cell differentiation
. They also take part in signal transduction
.
, which are important for the formation of stable dimers.
The N-terminus 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 C-terminus of this domain. The C-terminal part of the sHsps consists of the above mentioned α-crystallin domain, followed by a variable sequence with high motility and flexibility.
This C-terminal tail appears in many mammalian sHsps (e.g. mouse Hsp25, αA-crystallin) and has no homology. 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.
, which are formed by two α-crystallin-domains of neighbouring monomers, which was shown with the proteins MjHSP16.5 from Methanocaldococcus jannaschii
and wheat Hsp16.9. The stable dimers aggregate to tetramers and finally form unstable oligomers.
The oligomerization of Hsp27 is a dynamic process: There is a balance between stable dimers respectively tetramers and instable oligomers (up to 800 kDa) consisting of 16 to 32 subunits and a high exchange rate of subunits. The oligomerization depends on the physiology of the cells, the phosphorylation
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 cascade by differentiating agents, mitogens, inflammatory
cytokines such as TNFα and IL-1β, hydrogen peroxide
and other oxidants, 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
cells growing in vivo or growing at confluence in vitro is dependent on cell-cell contact, but not on the phosphorylation status.
In all probability, the oligomerization status is connected with the chaperone activity: aggregates of large oligomers have high chaperone activity, whereas dimers have no chaperone activity. Therefore it is clear, that a formation of large aggregates takes place under heat shock.
s, especially all types of muscle
cells. It is located mainly in the cytosol
, but also in the perinuclear region, endoplasmatic reticulum, and nucleus
. 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/neurodegenerative diseases and various cancers was observed. High expression levels possibly are in inverse relation with cell proliferation, metastasis
, and resistance to chemotherapy
. High levels of Hsp27 were also found in sera of breast cancer
patients; therefore Hsp27 could be a potential diagnostic marker.
-independent chaperone by inhibiting protein aggregation and by stabilizing partially denatured proteins, which ensures refolding by the Hsp70
-complex.
Hsp27 is also involved in the apoptotic
signalling pathway. Hsp27 interacts with the outer mitochondrial
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.
A well documented function of Hsp27 is the interaction with actin
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
.
Another function of Hsp27 is the activation of the proteasome
. It speeds up the degradation of irreversibly denatured proteins and junkproteins by binding to ubiquitin
ated proteins and to the 26S proteasome. Hsp27 enhances the activation of the NF-κB 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
and to raise glutathione
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
s, normal B-cells, B-lymphoma
cells, osteoblast
s, keratinocyte
s, neuron
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.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the HSPB1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Hsp27 is a chaperone of the sHsp (small heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
) group among ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
, α-crystallin
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 cancer tumors....
, Hsp20
Hsp20
Heat shock protein Hsp20 is a family of heat shock proteins.Prokaryotic and eukaryotic organisms respond to heat shock or other environmental stress by inducing the synthesis of proteins collectively known as heat-shock proteins . Amongst them is a family of proteins with an average molecular...
and others. The common functions of sHsps are chaperone activity, thermotolerance, inhibition of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, regulation of cell development, and cell differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
. They also take part in signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
.
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 at the C-terminus. These sequences consist of 80 to 100 residues with a homology between 20% and 60% and form β-sheetsBeta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
, which are important for the formation of stable dimers.
The N-terminus 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 C-terminus of this domain. The C-terminal part of the sHsps consists of the above mentioned α-crystallin domain, followed by a variable sequence with high motility and flexibility.
This C-terminal tail appears in many mammalian sHsps (e.g. mouse Hsp25, αA-crystallin) and has no homology. 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.
Oligomerization
The N-terminus with its WD/EPF-region is essential for the development of high molecular oligomers, which exclusively have chaperone activity in vitro. Hsp27-oligomers probably consist of stable dimersProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, which are formed by two α-crystallin-domains of neighbouring monomers, which was shown with the proteins MjHSP16.5 from Methanocaldococcus jannaschii
Methanocaldococcus
In taxonomy, Methanocaldococcus is a genus of the Methanocaldococcaceae.Methanocaldococcus formerly known as Methanococcus is a genus of coccoid methanogens. They are all mesophiles, except the thermophilic M. thermolithotrophicus and the hyperthermophilic M. jannaschii...
and wheat Hsp16.9. The stable dimers aggregate to tetramers and finally form unstable oligomers.
The oligomerization of Hsp27 is a dynamic process: There is a balance between stable dimers respectively tetramers and instable oligomers (up to 800 kDa) consisting of 16 to 32 subunits and a high exchange rate of subunits. The oligomerization depends on the physiology of the cells, the phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
status of Hsp27 and the exposure to stress. Stress induces an increase of expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
(after hours) and phosphorylation (after several minutes) of Hsp27. Stimulation of the p38 MAP kinase cascade by differentiating agents, mitogens, inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
cytokines such as TNFα and IL-1β, hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
and other oxidants, 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
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells growing in vivo or growing at confluence in vitro is dependent on cell-cell contact, but not on the phosphorylation status.
In all probability, the oligomerization status is connected with the chaperone activity: aggregates of large oligomers have high chaperone activity, whereas dimers have no chaperone activity. Therefore it is clear, that a formation of large aggregates takes place under heat shock.
Cellular Localization
Hsp27 appears in many cell typeCell type
A cell type is a distinct morphological or functional form of cell. When a cell switches state from one cell type to another, it undergoes cellular differentiation. A list of distinct cell types in the adult human body may include several hundred distinct types.-References:...
s, especially all types of muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
cells. It is located mainly in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
, but also in the perinuclear region, endoplasmatic reticulum, and nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
. 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/neurodegenerative diseases and various cancers was observed. High expression levels possibly are in inverse relation with cell proliferation, metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
, and resistance to chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. High levels of Hsp27 were also found in sera of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
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 ATPAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
-independent chaperone by inhibiting protein aggregation and by stabilizing partially denatured proteins, which ensures refolding by the Hsp70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...
-complex.
Hsp27 is also involved in the apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
signalling pathway. Hsp27 interacts with the outer mitochondrial
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
membranes and interferes with the activation of cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
/Apaf-1/dATP complex and therefore inhibits the activation of procaspase-9
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
. The phosphorylated form of Hsp27 inhibits Daxx
Death associated protein 6
Death-associated protein 6 also known as DAXX is a protein that in humans is encoded by the DAXX gene.- Function :DAXX, a death-domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death receptor Fas...
apoptotic protein and prevents the association of Daxx with Fas and Ask1.
A well documented function of Hsp27 is the interaction with actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
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
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
.
Another function of Hsp27 is the activation of the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
. It speeds up the degradation of irreversibly denatured proteins and junkproteins by binding to ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
ated proteins and to the 26S proteasome. Hsp27 enhances the activation of the NF-κB 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
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
and to raise glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
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 cell
Embryonic stem cells are pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells...
s, normal B-cells, B-lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
cells, osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
s, keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...
s, neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
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.
Interactions
Hsp27 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- CRYAACRYAAAlpha-crystallin A chain is a protein that in humans is encoded by the CRYAA gene.-Interactions:CRYAA has been shown to interact with CRYBB2, Hsp27, CRYGC and CRYAB.-Further reading:...
, - CRYABCRYABAlpha-crystallin B chain is a protein that in humans is encoded by the CRYAB gene.-Interactions:CRYAB has been shown to interact with CRYBB2, Hsp27, HSPB2, CRYGC, PSMA3 and CRYAA.-External links:* -Further reading:...
, - CRYBB2CRYBB2Beta-crystallin B2 is a protein that in humans is encoded by the CRYBB2 gene.-Interactions:CRYBB2 has been shown to interact with Hsp27, CRYGC, CRYAA and CRYAB.-Further reading:...
, - HNRPDHNRPDHeterogeneous nuclear ribonucleoprotein D0 is a protein that in humans is encoded by the HNRNPD gene.-Interactions:HNRPD has been shown to interact with SAFB and Hsp27.-Further reading:...
- HSPB8HSPB8Heat shock protein beta-8 is a protein that in humans is encoded by the HSPB8 gene.-Interactions:HSPB8 has been shown to interact with Hsp27 and HSPB2.-External links:*...
, and - TGFB1I1TGFB1I1Transforming growth factor beta-1-induced transcript 1 protein is a protein that in humans is encoded by the TGFB1I1 gene.-Interactions:TGFB1I1 has been shown to interact with PTPN12, PTK2, Androgen receptor, PTK2B, Dopamine transporter and Hsp27....
.