Hsp70
Encyclopedia
The 70 kilodalton heat shock proteins (Hsp70s) are a family of ubiquitously expressed heat shock protein
s. Proteins with similar structure exist in virtually all living organisms. The Hsp70s are an important part of the cell's machinery for protein folding, and help to protect cells from stress.
:
s, the substrate binding domain of Hsp70 recognizes sequences of hydrophobic amino acid residues, and interacts with them. This spontaneous interaction is reversible, and in the ATP bound state Hsp70 may relatively freely bind and release peptides. However, the presence of a peptide in the binding domain stimulates the ATPase activity of Hsp70, increasing its normally-slow rate of ATP hydrolysis. When ATP is hydrolyzed to ADP the binding pocket of Hsp70 closes, tightly binding the now-trapped peptide chain. Further speeding ATP hydrolysis are the so-called J-domain cochaperones: primarily Hsp40
in eukaryotes, and DnaJ in prokaryotes. These cochaperones dramatically increase the ATPase activity of Hsp70 in the presence of interacting peptides.
By binding tightly to partially-synthesized peptide sequences (incomplete proteins), Hsp70 prevents them from aggregating and being rendered nonfunctional. Once the entire protein is synthesized, a nucleotide exchange factor
(BAG-1
and HspBP1
are among those which have been identified) stimulates the release of ADP and binding of fresh ATP, opening the binding pocket. The protein is then free to fold on its own, or to be transferred to other chaperones for further processing. HOP
(the Hsp70/Hsp90 Organizing Protein) can bind to both Hsp70 and Hsp90 at the same time, and mediates the transfer of peptides from Hsp70 to Hsp90.
Hsp70 also aids in transmembrane transport of proteins, by stabilizing them in a partially-folded state.
Hsp70 proteins can act to protect cells from thermal or oxidative stress. These stresses normally act to damage proteins, causing partial unfolding and possible aggregation. By temporarily binding to hydrophobic residues exposed by stress, Hsp70 prevents these partially-denatured proteins from aggregating, and allows them to refold. Low ATP is characteristic of heat shock and sustained binding is seen as aggregation suppression, while recovery from heat shock involves substrate binding and nucleotide cycling. In a thermophile anaerobe (Thermotoga maritima) the Hsp70 demonstrates redox sensitive binding to model peptides, suggesting a second mode of binding regulation based on oxidative stress.
Hsp70 seems to be able to participate in disposal of damaged or defective proteins. Interaction with CHIP
(Carboxyl-terminus of Hsp70 Interacting Protein)–an E3 ubiquitin ligase
–allows Hsp70 to pass proteins to the cell's ubiquitin
ation and proteolysis
pathways.
Finally, in addition to improving overall protein integrity, Hsp 70 directly inhibits apoptosis. One hallmark of apoptosis is the release of cytochrome c, which then recruits Apaf-1 and dATP/ATP into an apoptosome complex. This complex then cleaves procaspase-9, activating caspase-9 and eventually inducing apoptosis via caspase-3 activation. Hsp 70 inhibits this process by blocking the recruitment of procaspase-9 to the Apaf-1/dATP/cytochrome c apoptosome complex. It does not bind directly to the procaspase-9 binding site, but likely induces a conformational change that renders procaspase-9 binding less favorable. Hsp70 is shown to interact with Endoplasmic reticulum stress sensor protein IRE1alpha thereby protecting the cells from ER stress - induced apoptosis. This interaction prolonged the splicing of XBP-1 mRNA thereby inducing transcriptional upregulation of targets of spliced XBP-1 like EDEM1, ERdj4 and P58IPK rescuing the cells from apoptosis. Other studies suggest that Hsp 70 may play an anti-apoptotic role at other steps, but is not involved in Fas-ligand-mediated apoptosis (although Hsp 27 is). Therefore, Hsp 70 not only saves important components of the cell (the proteins) but also directly saves the cell as a whole. Considering that stress-response proteins (like Hsp 70) evolved before apoptotic machinery, Hsp 70’s direct role in inhibiting apoptosis provides an interesting evolutionary picture of how more recent (apoptotic) machinery accommodated previous machinery (Hsps), thus aligning the improved integrity of a cell’s proteins with the improved chances of that particular cell’s survival.
Eukaryotic organisms express several slightly different Hsp70 proteins. All share the common domain structure, but each has a unique pattern of expression or subcellular localization. These are, among others:
The following is a list of human Hsp70 genes and their corresponding proteins:
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...
s. Proteins with similar structure exist in virtually all living organisms. The Hsp70s are an important part of the cell's machinery for protein folding, and help to protect cells from stress.
Discovery
Members of the Hsp70 family are strongly upregulated by heat stress and toxic chemicals, particularly heavy metals such as arsenic, cadmium, copper, mercury, etc. Hsp70 was originally discovered by FM Ritossa in the 1960s when a lab worker accidentally boosted the incubation temperature of Drosophila (fruit flies). When examining the chromosomes, Ritossa found a "puffing pattern" that indicated the elevated gene transcription of an unknown protein. This was later described as the "Heat Shock Response" and the proteins were termed the "Heat Shock Proteins" (Hsps).Structure
The Hsp70 proteins have three major functional domainsProtein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
:
- N-terminal ATPaseATPaseATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
domain – binds ATP (Adenosine triphosphateAdenosine triphosphateAdenosine-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...
) and hydrolyzes it to ADP (Adenosine diphosphateAdenosine diphosphateAdenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
). The exchange of ATP drives conformational changes in the other two domains. - Substrate binding domain – contains a groove with an affinity for neutral, hydrophobic amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues. The groove is long enough to interact with peptides up to seven residues in length. - C-terminal domain – rich in alpha helical structureAlpha helixA common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
acts as a 'lid' for the substrate binding domain. When an Hsp70 protein is ATP bound, the lid is open and peptides bind and release relatively rapidly. When Hsp70 proteins are ADP bound, the lid is closed, and peptides are tightly bound to the substrate binding domain.
Function and regulation
When not interacting with a substrate peptide, Hsp70 is usually in an ATP bound state. Hsp70 by itself is characterized by a very weak ATPase activity, such that spontaneous hydrolysis will not occur for many minutes. As newly synthesized proteins emerge from the ribosomeRibosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
s, the substrate binding domain of Hsp70 recognizes sequences of hydrophobic amino acid residues, and interacts with them. This spontaneous interaction is reversible, and in the ATP bound state Hsp70 may relatively freely bind and release peptides. However, the presence of a peptide in the binding domain stimulates the ATPase activity of Hsp70, increasing its normally-slow rate of ATP hydrolysis. When ATP is hydrolyzed to ADP the binding pocket of Hsp70 closes, tightly binding the now-trapped peptide chain. Further speeding ATP hydrolysis are the so-called J-domain cochaperones: primarily Hsp40
DNAJB1
DnaJ homolog subfamily B member 1 is a protein that in humans is encoded by the DNAJB1 gene.-Interactions:DNAJB1 has been shown to interact with STUB1 and HSPA4.-Further reading:...
in eukaryotes, and DnaJ in prokaryotes. These cochaperones dramatically increase the ATPase activity of Hsp70 in the presence of interacting peptides.
By binding tightly to partially-synthesized peptide sequences (incomplete proteins), Hsp70 prevents them from aggregating and being rendered nonfunctional. Once the entire protein is synthesized, a nucleotide exchange factor
Nucleotide exchange factor
Nucleotide exchange factors are proteins that stimulate the exchange of nucleoside diphosphates for nucleoside triphosphates bound to other proteins.-Function:...
(BAG-1
BAG1
BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.BAG gene has been implicated in age related neurodegenerative diseases as Alzheimer's...
and HspBP1
HSPBP1
Hsp70-binding protein 1 is a protein that in humans is encoded by the HSPBP1 gene.-Interactions:HSPBP1 has been shown to interact with HSPA8 and HSPA4.-Further reading:...
are among those which have been identified) stimulates the release of ADP and binding of fresh ATP, opening the binding pocket. The protein is then free to fold on its own, or to be transferred to other chaperones for further processing. HOP
Hop (protein)
Hop, occasionally written HOP, is an abbreviation for Hsp70-Hsp90 Organizing Protein. It functions as a co-chaperone which reversibly links together the protein chaperones Hsp70 and Hsp90....
(the Hsp70/Hsp90 Organizing Protein) can bind to both Hsp70 and Hsp90 at the same time, and mediates the transfer of peptides from Hsp70 to Hsp90.
Hsp70 also aids in transmembrane transport of proteins, by stabilizing them in a partially-folded state.
Hsp70 proteins can act to protect cells from thermal or oxidative stress. These stresses normally act to damage proteins, causing partial unfolding and possible aggregation. By temporarily binding to hydrophobic residues exposed by stress, Hsp70 prevents these partially-denatured proteins from aggregating, and allows them to refold. Low ATP is characteristic of heat shock and sustained binding is seen as aggregation suppression, while recovery from heat shock involves substrate binding and nucleotide cycling. In a thermophile anaerobe (Thermotoga maritima) the Hsp70 demonstrates redox sensitive binding to model peptides, suggesting a second mode of binding regulation based on oxidative stress.
Hsp70 seems to be able to participate in disposal of damaged or defective proteins. Interaction with CHIP
STUB1
STUB1 , also known as CHIP , is a human gene.- Function :...
(Carboxyl-terminus of Hsp70 Interacting Protein)–an E3 ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
–allows Hsp70 to pass proteins to the cell's 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...
ation and proteolysis
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...
pathways.
Finally, in addition to improving overall protein integrity, Hsp 70 directly inhibits apoptosis. One hallmark of apoptosis is the release of cytochrome c, which then recruits Apaf-1 and dATP/ATP into an apoptosome complex. This complex then cleaves procaspase-9, activating caspase-9 and eventually inducing apoptosis via caspase-3 activation. Hsp 70 inhibits this process by blocking the recruitment of procaspase-9 to the Apaf-1/dATP/cytochrome c apoptosome complex. It does not bind directly to the procaspase-9 binding site, but likely induces a conformational change that renders procaspase-9 binding less favorable. Hsp70 is shown to interact with Endoplasmic reticulum stress sensor protein IRE1alpha thereby protecting the cells from ER stress - induced apoptosis. This interaction prolonged the splicing of XBP-1 mRNA thereby inducing transcriptional upregulation of targets of spliced XBP-1 like EDEM1, ERdj4 and P58IPK rescuing the cells from apoptosis. Other studies suggest that Hsp 70 may play an anti-apoptotic role at other steps, but is not involved in Fas-ligand-mediated apoptosis (although Hsp 27 is). Therefore, Hsp 70 not only saves important components of the cell (the proteins) but also directly saves the cell as a whole. Considering that stress-response proteins (like Hsp 70) evolved before apoptotic machinery, Hsp 70’s direct role in inhibiting apoptosis provides an interesting evolutionary picture of how more recent (apoptotic) machinery accommodated previous machinery (Hsps), thus aligning the improved integrity of a cell’s proteins with the improved chances of that particular cell’s survival.
Family members
Prokaryotes express three Hsp70 proteins: DnaK, HscA (Hsc66), and HscC (Hsc62).Eukaryotic organisms express several slightly different Hsp70 proteins. All share the common domain structure, but each has a unique pattern of expression or subcellular localization. These are, among others:
- Hsc70 (Hsp73/HSPA8) is a constitutively expressed chaperone protein. It typically makes up one to three percent of total cellular protein.
- Hsp70HSPA1AHeat shock 70 kDa protein 1 is a protein that in humans is encoded by the HSPA1A gene.-Interactions:HSPA1A has been shown to interact with ASK1, STUB1, MSR1, BAG3, Parkin , Fanconi anemia, complementation group C, GPR37, HSF1 and AIFM1....
(encoded by three very closely related paralogs: HSPA1A, HSPA1B, and HSPA1L) is a stress-induced protein. High levels can be produced by cells in response to hyperthermia, oxidative stress, and changes in pHPHIn chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
. - Binding immunoglobulin proteinBinding immunoglobulin proteinBinding immunoglobulin protein also known as 78 kDa glucose-regulated protein or heat shock 70 kDa protein 5 is a HSP70 molecular chaperone located in the lumen of the endoplasmic reticulum that binds newly-synthesized proteins as they are translocated into the ER, and maintains them in a state...
(BiP or Grp78) is a protein localized to the endoplasmic reticulumEndoplasmic reticulumThe endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. It is involved in protein folding there, and can be upregulated in response to stress or starvation. - mtHsp70HSPA9Stress-70 protein, mitochondrial is a protein that in humans is encoded by the HSPA9 gene.-Interactions:HSPA9 has been shown to interact with FGF1 and P53.- External links :...
or Grp75 is the mitochondrialMitochondrionIn 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...
Hsp70.
The following is a list of human Hsp70 genes and their corresponding proteins:
| gene | protein | synonyms | subcellular location |
|---|---|---|---|
| HSPA1A HSPA1A Heat shock 70 kDa protein 1 is a protein that in humans is encoded by the HSPA1A gene.-Interactions:HSPA1A has been shown to interact with ASK1, STUB1, MSR1, BAG3, Parkin , Fanconi anemia, complementation group C, GPR37, HSF1 and AIFM1.... |
Hsp70 | HSP70-1, Hsp72 | Nuc 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... /Cyto |
| HSPA1B HSPA1B Heat shock 70kDa protein 1B, also known as HSPA1B, is a human gene. This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family.-Function:... |
Hsp70 | HSP70-2 | Nuc/Cyto |
| HSPA1L HSPA1L Heat shock 70 kDa protein 1L is a protein that in humans is encoded by the HSPA1L gene.-Further reading:... |
Hsp70 | ? | |
| HSPA2 HSPA2 Heat shock-related 70 kDa protein 2 is a protein that in humans is encoded by the HSPA2 gene.-Further reading:... |
Hsp70-2 | ? | |
| HSPA4 HSPA4 Heat shock 70 kDa protein 4 is a protein that in humans is encoded by the HSPA4 gene.The protein encoded by this gene was originally suggested to be a member of the heat shock protein 70 family... |
Hsp70-4 | ? | |
| HSPA4L HSPA4L Heat shock 70 kDa protein 4L is a protein that in humans is encoded by the HSPA4L gene.... |
Hsp70-4L | ? | |
| HSPA5 Binding immunoglobulin protein Binding immunoglobulin protein also known as 78 kDa glucose-regulated protein or heat shock 70 kDa protein 5 is a HSP70 molecular chaperone located in the lumen of the endoplasmic reticulum that binds newly-synthesized proteins as they are translocated into the ER, and maintains them in a state... |
Hsp70-5 | BiP/Grp78 | ER Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... |
| HSPA6 HSPA6 Heat shock 70 kDa protein 6 is a protein that in humans is encoded by the HSPA6 gene.-Further reading:... |
Hsp70-6 | ? | |
| HSPA7 HSPA7 Heat shock 70kDa protein 7 also known as HSPA7 is a human gene. The protein encoded by this gene is a member of the Hsp70 family of heat shock proteins.... |
Hsp70-7 | ? | |
| HSPA8 | Hsp70-8 | Hsc70 | Nuc/Cyto |
| HSPA9 HSPA9 Stress-70 protein, mitochondrial is a protein that in humans is encoded by the HSPA9 gene.-Interactions:HSPA9 has been shown to interact with FGF1 and P53.- External links :... |
Hsp70-9 | Grp75/mtHsp70 | Mito 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... |
| HSPA12A HSPA12A Heat shock 70kDa protein 12A also known as HSPA12A is a human gene. The protein encoded by this gene is a member of the Hsp70 family of heat shock proteins.... |
Hsp70-12a | ? | |
| HSPA14 HSPA14 Heat shock 70 kDa protein 14 also known as HSP70-like protein 1 or heat shock protein HSP60 is a protein that in humans is encoded by the HSPA14 gene.... |
Hsp70-14 | ? |
See also
- Mitochondrial import stimulation factor
- Heat shock protein 70 (Hsp70) internal ribosome entry site (IRES)Heat shock protein 70 (Hsp70) internal ribosome entry site (IRES)The heat shock protein 70 internal ribosome entry site is an RNA element that allows cap independent translation during conditions such as heat shock and stress. It has been shown that the 216 nucleotide long 5' UTR contains internal ribosome entry site activity....