Summary: Hsp70 protein
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Hsp70 Edit Wikipedia article
Structure of the ATPase fragment of a 70K heat-shock cognate protein.
The 70 kilodalton heat shock proteins (Hsp70s) are a family of ubiquitously expressed heat shock proteins. 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.
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).
The Hsp70 proteins have three major functional domains:
- N-terminal ATPase domain – binds ATP (Adenosine triphosphate) and hydrolyzes it to ADP (Adenosine diphosphate). 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 acid residues. The groove is long enough to interact with peptides up to seven residues in length.
- C-terminal domain – rich in alpha helical structure 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 ribosomes, 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 ubiquitination 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.
 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.
- Hsp70 (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 pH.
- Binding immunoglobulin protein (BiP or Grp78) is a protein localized to the endoplasmic reticulum. It is involved in protein folding there, and can be upregulated in response to stress or starvation.
- mtHsp70 or Grp75 is the mitochondrial Hsp70.
The following is a list of human Hsp70 genes and their corresponding proteins:
 See also
- Mitochondrial import stimulation factor
- Heat shock protein 70 (Hsp70) internal ribosome entry site (IRES)
- Flaherty KM, DeLuca-Flaherty C, McKay DB (August 1990). "Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein". Nature 346 (6285): 623–8. doi:10.1038/346623a0. PMID 2143562.
- Tavaria M, Gabriele T, Kola I, Anderson RL (April 1996). "A hitchhiker's guide to the human Hsp70 family". Cell Stress Chaperones 1 (1): 23–8. doi:10.1379/1466-1268(1996)001<0023:AHSGTT>2.3.CO;2. PMC 313013. PMID 9222585.
- Morano KA (October 2007). "New tricks for an old dog: the evolving world of Hsp70". Ann. N. Y. Acad. Sci. 1113: 1–14. doi:10.1196/annals.1391.018. PMID 17513460.
- Ritossa F (1962). "A new puffing pattern induced by temperature shock and DNP in drosophila". Cellular and Molecular Life Sciences (CMLS) 18 (12): 571–573. doi:10.1007/BF02172188.
- Ritossa F (June 1996). "Discovery of the heat shock response". Cell Stress Chaperones 1 (2): 97–8. doi:10.1379/1466-1268(1996)001<0097:DOTHSR>2.3.CO;2. PMC 248460. PMID 9222594.
- Wegele H, Müller L, Buchner J (2004). "Hsp70 and Hsp90 – a relay team for protein folding". Rev. Physiol. Biochem. Pharmacol. Reviews of Physiology, Biochemistry and Pharmacology 151: 1–44. doi:10.1007/s10254-003-0021-1. ISBN 978-3-540-22096-1. PMID 14740253.
- Lüders J, Demand J, Höhfeld J (February 2000). "The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome". J. Biol. Chem. 275 (7): 4613–7. doi:10.1074/jbc.275.7.4613. PMID 10671488.
- Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM, Green DR (August 2000). "Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome". Nat. Cell Biol. 2 (8): 469–75. doi:10.1038/35019501. PMID 10934466.
- Gupta S, Deepti A, Deegan S, Lisbona F, Hetz C, Samali A (July 2010). "HSP72 Protects Cells from ER Stress-induced Apoptosis via Enhancement of IRE1α-XBP1 Signaling through a Physical Interaction". In Kelly, Jeffrey W. PLoS Biol. 8 (7): e1000410. doi:10.1371/journal.pbio.1000410. PMC 2897763. PMID 20625543.
- Ricaniadis N, Kataki A, Agnantis N, Androulakis G, Karakousis CP (February 2001). "Long-term prognostic significance of HSP-70, c-myc and HLA-DR expression in patients with malignant melanoma". Eur J Surg Oncol 27 (1): 88–93. doi:10.1053/ejso.1999.1018. PMID 11237497.
- Ramp U, Mahotka C, Heikaus S, Shibata T, Grimm MO, Willers R, Gabbert HE (October 2007). "Expression of heat shock protein 70 in renal cell carcinoma and its relation to tumor progression and prognosis". Histol. Histopathol. 22 (10): 1099–107. PMID 17616937.
- "Heat shock proteins and cancer". HealthValue. Retrieved 2009-05-26.
- Yoshimune K, Yoshimura T, Nakayama T, Nishino T, Esaki N (May 2002). "Hsc62, Hsc56, and GrpE, the third Hsp70 chaperone system of Escherichia coli". Biochem. Biophys. Res. Commun. 293 (5): 1389–95. doi:10.1016/S0006-291X(02)00403-5. PMID 12054669.
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Hsp70 protein Provide feedback
Hsp70 chaperones help to fold many proteins. Hsp70 assisted folding involves repeated cycles of substrate binding and release. Hsp70 activity is ATP dependent. Hsp70 proteins are made up of two regions: the amino terminus is the ATPase domain and the carboxyl terminus is the substrate binding region.
Internal database links
|Similarity to PfamA using HHSearch:||Hydantoinase_A MreB_Mbl DDR FtsA|
External database links
|Transporter classification:||1.A.33 3.A.9|
This tab holds annotation information from the InterPro database.
InterPro entry IPR013126
Heat shock proteins, Hsp70 chaperones help to fold many proteins. Hsp70 assisted folding involves repeated cycles of substrate binding and release. Hsp70 activity is ATP dependent. Hsp70 proteins are made up of two regions: the amino terminus is the ATPase domain and the carboxyl terminus is the substrate binding region [PUBMED:9476895].
Hsp70 proteins have an average molecular weight of 70 kDa [PUBMED:2686623, PUBMED:2944601, PUBMED:3282176]. In most species, there are many proteins that belong to the Hsp70 family. Some of these are only expressed under stress conditions (strictly inducible), while some are present in cells under normal growth conditions and are not heat-inducible (constitutive or cognate) [PUBMED:2143562, PUBMED:2841196]. Hsp70 proteins can be found in different cellular compartments(nuclear, cytosolic, mitochondrial, endoplasmic reticulum, for example).
This entry represents the Hsp70 family, and includes chaperone protein DnaK and luminal-binding proteins.
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|Author:||Bateman A, Sonnhammer ELL|
|Number in seed:||33|
|Number in full:||23002|
|Average length of the domain:||370.00 aa|
|Average identity of full alignment:||30 %|
|Average coverage of the sequence by the domain:||85.27 %|
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build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||15|
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