HSPA1A

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Heat shock 70kDa protein 1A
Protein HSPA1A PDB 1hjo.png
PDB rendering based on 1hjo.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HSPA1A ; HEL-S-103; HSP70-1; HSP70-1A; HSP70I; HSP72; HSPA1
External IDs OMIM140550 MGI99517 HomoloGene74294 IUPHAR: 2539 ChEMBL: 5460 GeneCards: HSPA1A Gene
Orthologs
Species Human Mouse
Entrez 3303 193740
Ensembl ENSG00000204388 ENSMUSG00000091971
UniProt P08107 Q61696
RefSeq (mRNA) NM_005345 NM_010479
RefSeq (protein) NP_005336 NP_034609
Location (UCSC) Chr 6:
31.78 – 31.79 Mb
Chr 17:
34.97 – 34.97 Mb
PubMed search [1] [2]

Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene.[1][2] As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins.[1][2] In addition, Hsp72 also facilitates DNA repair.[3] Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[2][4] It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.[5][6][4]

Function[edit]

This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 (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.[1] 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.[2] Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[2][4]

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.[2] Hsp72 also protects against DNA damage and participates in DNA repair, including base excision repair (BER) and nucleotide excision repair (NER).[3] Furthermore, this protein enhances antigen-specific tumor immunity by facilitating more efficient antigen presentation to cytotoxic T cells.[4] It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins.[1] Finally, Hsp72 can protect against disrupted metabolic homeostasis by inducing production of pro-inflammatory cytokines, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in immune cells, thereby reducing inflammation and improving skeletal muscle oxidation.[5][7] Though at very low levels under normal conditions, HSP72 expression greatly increases under stress, effectively protecting cells from adverse effects in various pathological states.[8]

Clinical Significance[edit]

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), staurosporin, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colonic tumors, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers.[4] Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation.[2][4] As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials.[4] One treatment, a Hsp72/AFP recombined vaccine, elicited robust protective immunity against AFP-expressing tumors in mice experiments. Therefore, the vaccine holds promise for treating hepatocellular carcinoma.[4] Alternatively, overexpression of Hsp70 can mitigate the effects of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s corea, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge.[2]

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.[5] Additionally, Hsp72 has been associated with another inflammatory condition, rheumatoid arthritis, and could be implemented to help diagnose and monitor disease activity in patients.[6]

Interactions[edit]

HSPA1A has been shown to interact with:

See also[edit]

References[edit]

  1. ^ a b c d "Entrez Gene: HSPA1A heat shock 70kDa protein 1A". 
  2. ^ a b c d e f g h i Mayer MP, Bukau B (Mar 2005). "Hsp70 chaperones: cellular functions and molecular mechanism". Cellular and Molecular Life Sciences 62 (6). doi:10.1007/s00018-004-4464-6. PMC 2773841. PMID 15770419. 
  3. ^ a b c d Duan Y, Huang S, Yang J, Niu P, Gong Z, Liu X et al. (Mar 2014). "HspA1A facilitates DNA repair in human bronchial epithelial cells exposed to Benzo[a]pyrene and interacts with casein kinase 2". Cell Stress & Chaperones 19 (2). doi:10.1007/s12192-013-0454-7. PMID 23979991. 
  4. ^ a b c d e f g h Wang X, Wang Q, Lin H, Li S, Sun L, Yang Y (Feb 2013). "HSP72 and gp96 in gastroenterological cancers". Clinica Chimica Acta; International Journal of Clinical Chemistry 417. doi:10.1016/j.cca.2012.12.017. PMID 23266770. 
  5. ^ a b c Henstridge DC, Whitham M, Febbraio MA (Nov 2014). "Chaperoning to the metabolic party: The emerging therapeutic role of heat-shock proteins in obesity and type 2 diabetes". Molecular Metabolism 3 (8). doi:10.1016/j.molmet.2014.08.003. PMID 25379403. 
  6. ^ a b Najafizadeh SR, Ghazizadeh Z, Nargesi AA, Mahdavi M, Abtahi S, Mirmiranpour H et al. (Mar 2015). "Analysis of serum heat shock protein 70 (HSPA1A) concentrations for diagnosis and disease activity monitoring in patients with rheumatoid arthritis". Cell Stress & Chaperones. doi:10.1007/s12192-015-0578-z. PMID 25739548. 
  7. ^ Gibson OR, Dennis A, Parfitt T, Taylor L, Watt PW, Maxwell NS (May 2014). "Extracellular Hsp72 concentration relates to a minimum endogenous criteria during acute exercise-heat exposure". Cell Stress & Chaperones 19 (3). doi:10.1007/s12192-013-0468-1. PMC 3982022. PMID 24085588. 
  8. ^ Ryu DS, Yang H, Lee SE, Park CS, Jin YH, Park YS (Nov 2013). "Crotonaldehyde induces heat shock protein 72 expression that mediates anti-apoptotic effects in human endothelial cells". Toxicology Letters 223 (2). doi:10.1016/j.toxlet.2013.09.010. PMID 24070736. 
  9. ^ Ruchalski K, Mao H, Singh SK, Wang Y, Mosser DD, Li F et al. (December 2003). "HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells". Am. J. Physiol., Cell Physiol. 285 (6): C1483–93. doi:10.1152/ajpcell.00049.2003. PMID 12930708. 
  10. ^ Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N et al. (September 2001). "Heat-shock protein 70 antagonizes apoptosis-inducing factor". Nat. Cell Biol. 3 (9): 839–43. doi:10.1038/ncb0901-839. PMID 11533664. 
  11. ^ Park HS, Cho SG, Kim CK, Hwang HS, Noh KT, Kim MS et al. (November 2002). "Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1". Mol. Cell. Biol. 22 (22): 7721–30. doi:10.1128/mcb.22.22.7721-7730.2002. PMC 134722. PMID 12391142. 
  12. ^ Doong H, Price J, Kim YS, Gasbarre C, Probst J, Liotta LA et al. (September 2000). "CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70". Oncogene 19 (38): 4385–95. doi:10.1038/sj.onc.1203797. PMID 10980614. 
  13. ^ Antoku K, Maser RS, Scully WJ, Delach SM, Johnson DE (September 2001). "Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein". Biochem. Biophys. Res. Commun. 286 (5): 1003–10. doi:10.1006/bbrc.2001.5512. PMID 11527400. 
  14. ^ Pang Q, Christianson TA, Keeble W, Koretsky T, Bagby GC (December 2002). "The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC". J. Biol. Chem. 277 (51): 49638–43. doi:10.1074/jbc.M209386200. PMID 12397061. 
  15. ^ Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H et al. (October 2003). "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Exp. Cell Res. 289 (2): 211–21. doi:10.1016/s0014-4827(03)00261-1. PMID 14499622. 
  16. ^ a b c Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI et al. (July 2002). "CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity". Mol. Cell 10 (1): 55–67. doi:10.1016/s1097-2765(02)00583-x. PMID 12150907. 
  17. ^ Shi Y, Mosser DD, Morimoto RI (March 1998). "Molecular chaperones as HSF1-specific transcriptional repressors". Genes Dev. 12 (5): 654–66. doi:10.1101/gad.12.5.654. PMC 316571. PMID 9499401. 
  18. ^ Zhou X, Tron VA, Li G, Trotter MJ (August 1998). "Heat shock transcription factor-1 regulates heat shock protein-72 expression in human keratinocytes exposed to ultraviolet B light". J. Invest. Dermatol. 111 (2): 194–8. doi:10.1046/j.1523-1747.1998.00266.x. PMID 9699716. 
  19. ^ Nakamura T, Hinagata J, Tanaka T, Imanishi T, Wada Y, Kodama T et al. (January 2002). "HSP90, HSP70, and GAPDH directly interact with the cytoplasmic domain of macrophage scavenger receptors". Biochem. Biophys. Res. Commun. 290 (2): 858–64. doi:10.1006/bbrc.2001.6271. PMID 11785981. 
  20. ^ Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin LY et al. (June 1999). "Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions". Mol. Cell. Biol. 19 (6): 4535–45. PMC 104411. PMID 10330192. 

Further reading[edit]

External links[edit]