HSPA1A
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| Location (UCSC) | Chr 6: 31.82 – 31.82 Mb | Chr 17: 35.19 – 35.19 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Heat shock 70 kDa protein 1, also termed Hsp72, is a
Structure
This
The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket. The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical for allosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site for co-chaperones.[13]Function
This protein is a member of the Hsp70 family. In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles.[5] In order to properly fold non-native proteins, this protein interacts with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of free substrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state.[6] Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[6][8]
In addition to the process of protein folding, transport and degradation, this Hsp70 member can preserve the function of mutant proteins. Nonetheless, effects of these mutations can still manifest when Hsp70 chaperones are overwhelmed during stress conditions.
Along with its role in DNA repair, Hsp72 is also directly involved in
Clinical significance
The Hsp70 member proteins are important apoptotic constituents. During a normal
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα),
In Diabetes mellitus type 2 (T2DM), a small molecule activator of Hsp72 named BGP-15 has been shown to improve insulin sensitivity and inflammation in an insulin-resistant mouse model, increase mitochondrial volume, and improve metabolic homeostasis in a rat model of T2DM. BGP-15 has now proceeded to Phase 2b clinical trials and demonstrated no side-effects thus far. Though early speculation considered that Hsp72 expression might be affecting insulin sensitivity through a direct interaction with GLUT4, studies were unable to verify this link. Experiments did reveal that Hsp72 improved insulin sensitivity through stimulating glucose uptake during a hyperinsulemic-euglycemic clamp in T2DM patients.[9] Additionally, Hsp72 has been associated with another inflammatory condition, rheumatoid arthritis, and could be implemented to help diagnose and monitor disease activity in patients.[10]
Interactions
HSPA1A has been shown to
See also
- Heat shock proteins
- Hsp70
References
- ^ a b c ENSG00000204389, ENSG00000237724, ENSG00000235941, ENSG00000215328 GRCh38: Ensembl release 89: ENSG00000234475, ENSG00000204389, ENSG00000237724, ENSG00000235941, ENSG00000215328 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000091971 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d e "Entrez Gene: HSPA1A heat shock 70kDa protein 1A".
- ^ PMID 15770419.
- ^ PMID 23979991.
- ^ PMID 23266770.
- ^ PMID 25379403.
- ^ PMID 25739548.
- ^ S2CID 21164493.
- ^ PMID 25394481.
- ^ PMID 25058147.
- PMID 24085588.
- PMID 24070736.
- PMID 4561027.
- PMID 25379403.
- PMID 12930708.
- PMID 12391142.
- S2CID 28684205.
- PMID 11527400.
- PMID 12397061.
- PMID 14499622.
- ^ PMID 12150907.
- PMID 9499401.
- PMID 9699716.
- PMID 11785981.
- PMID 10330192.
Further reading
- Andersen JL, Planelles V (2005). "The role of Vpr in HIV-1 pathogenesis". Curr. HIV Res. 3 (1): 43–51. PMID 15638722.
- Zhao RY, Elder RT (2005). "Viral infections and cell cycle G2/M regulation". Cell Res. 15 (3): 143–9. PMID 15780175.
- Zhao RY, Bukrinsky M, Elder RT (2005). "HIV-1 viral protein R (Vpr) & host cellular responses". Indian J. Med. Res. 121 (4): 270–86. PMID 15817944.
- Muthumani K, Choo AY, Premkumar A, Hwang DS, Thieu KP, Desai BM, Weiner DB (2006). "Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism". Cell Death Differ. 12 (Suppl 1): 962–70. PMID 15832179.
- Grosz MD, Womack JE, Skow LC (1993). "Syntenic conservation of HSP70 genes in cattle and humans". Genomics. 14 (4): 863–8. PMID 1478667.
- Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E (1992). "Anti-androgens and the mutated androgen receptor of LNCaP cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation". Biochemistry. 31 (8): 2393–9. PMID 1540595.
- Abravaya K, Myers MP, Murphy SP, Morimoto RI (1992). "The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression". Genes Dev. 6 (7): 1153–64. PMID 1628823.
- Milner CM, Campbell RD (1990). "Structure and expression of the three MHC-linked HSP70 genes". Immunogenetics. 32 (4): 242–51. S2CID 9531492.
- Sargent CA, Dunham I, Trowsdale J, Campbell RD (1989). "Human major histocompatibility complex contains genes for the major heat shock protein HSP70". Proc. Natl. Acad. Sci. U.S.A. 86 (6): 1968–72. PMID 2538825.
- Wu B, Hunt C, Morimoto R (1985). "Structure and expression of the human gene encoding major heat shock protein HSP70". Mol. Cell. Biol. 5 (2): 330–41. PMID 2858050.
- Goate AM, Cooper DN, Hall C, Leung TK, Solomon E, Lim L (1987). "Localization of a human heat-shock HSP 70 gene sequence to chromosome 6 and detection of two other loci by somatic-cell hybrid and restriction fragment length polymorphism analysis". Hum. Genet. 75 (2): 123–8. S2CID 33788452.
- Hickey E, Brandon SE, Sadis S, Smale G, Weber LA (1986). "Molecular cloning of sequences encoding the human heat-shock proteins and their expression during hyperthermia". Gene. 43 (1–2): 147–54. PMID 3019832.
- Harrison GS, Drabkin HA, Kao FT, Hartz J, Hart IM, Chu EH, Wu BJ, Morimoto RI (1987). "Chromosomal location of human genes encoding major heat-shock protein HSP70" (PDF). Somat. Cell Mol. Genet. 13 (2): 119–30. S2CID 16069170.
- Drabent B, Genthe A, Benecke BJ (1987). "In vitro transcription of a human hsp 70 heat shock gene by extracts prepared from heat-shocked and non-heat-shocked human cells". Nucleic Acids Res. 14 (22): 8933–48. PMID 3786141.
- Hunt C, Morimoto RI (1985). "Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70". Proc. Natl. Acad. Sci. U.S.A. 82 (19): 6455–9. PMID 3931075.
- Liao J, Lowthert LA, Ghori N, Omary MB (1995). "The 70-kDa heat shock proteins associate with glandular intermediate filaments in an ATP-dependent manner". J. Biol. Chem. 270 (2): 915–22. PMID 7529764.
- Selkirk JK, Merrick BA, Stackhouse BL, He C (1995). "Multiple p53 protein isoforms and formation of oligomeric complexes with heat shock proteins Hsp70 and Hsp90 in the human mammary tumor, T47D, cell line". Appl. Theor. Electrophor. 4 (1): 11–8. PMID 7811761.
- Furlini G, Vignoli M, Re MC, Gibellini D, Ramazzotti E, Zauli G, La Placa M (1994). "Human immunodeficiency virus type 1 interaction with the membrane of CD4+ cells induces the synthesis and nuclear translocation of 70K heat shock protein". J. Gen. Virol. 75 (1): 193–9. PMID 7906708.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. PMID 8125298.
- Prapapanich V, Chen S, Toran EJ, Rimerman RA, Smith DF (1996). "Mutational analysis of the hsp70-interacting protein Hip". Mol. Cell. Biol. 16 (11): 6200–7. PMID 8887650.
External links
- HSPA1A+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P0DMV8 (Heat shock 70 kDa protein 1A) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: P0DMV9 (Heat shock 70 kDa protein 1B) at the PDBe-KB.
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