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Gene Review

HSPA8  -  heat shock 70kDa protein 8

Bos taurus

Synonyms: HSPA10, Hsc70
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Disease relevance of HSPA8

  • The recombinant 60-kDa fragment of rat hsc70 has been overexpressed in Escherichia coli [1].
  • Hsc70-binding peptides selected from a phage display peptide library that resemble organellar targeting sequences [2].

High impact information on HSPA8


Biological context of HSPA8

  • Structural replacement of active site monovalent cations by the epsilon-amino group of lysine in the ATPase fragment of bovine Hsc70 [6].
  • Steady-state solution small-angle X-ray scattering and kinetic fluorescence measurements on a 60-kDa fragment of Hsc70 show that point mutations K71M, E175S, D199S, and D206S in the nucleotide binding cleft impair the ability of ATP to induce a conformational change [7].
  • We have examined the roles of Hsc70 and auxilin in the uncoating of clathrin-coated vesicles (CCVs) during neuronal endocytosis [5].
  • A fragment containing auxilin's J domain associates in an ATP-dependent reaction with hsc70 to form a complex with a half-life of 8 min at 25 degrees C. When the clathrin binding domain and the J domain are recombined via dimerization of their GST moieties, cofactor activity is partially recovered [8].
  • Stable clathrin: uncoating protein (hsc70) complexes in intact neurons and their axonal transport [9].

Anatomical context of HSPA8

  • These studies establish that auxilin and Hsc70 participate in synaptic vesicle recycling in neurons and that an interaction between these proteins is required for CCV uncoating [5].
  • Although there is very little sequence identity between the two proteins, the structures of rabbit skeletal muscle actin (375-amino acid residues) and the 44-kDa ATPase fragment of the bovine 70-kDa heat shock cognate protein (HSC70; 386 residues) are very similar [10].
  • The 70-kDa heat shock cognate (Hsc70) chaperone plays a crucial role in protein (re-)folding and triage in the mammalian cytosol [11].
  • Precursor proteins were coimmunoprecipitated from the reticulocyte lysate containing the newly synthesized precursor proteins with an hsc70 antibody [12].
  • By using anti-DnaK antibodies we purified the DnaK homologue heat-shock cognate protein (Hsc70) from calf thymus to apparent homogeneity [13].

Associations of HSPA8 with chemical compounds

  • In the bovine Hsc70 ATPase fragment, mutation of cysteine 17 or aspartic acid 206 to lysine potentially allows the replacement of an active site potassium ion with the epsilon-amino nitrogen [6].
  • We conclude that the hydroxyl of Thr13 is essential for coupling ATP binding to a conformational change in Hsc70 [14].
  • We have mutated the equivalent resitude of the bovine heat shock cognate protein (Hsc70), Thr13, to serine, valine, and glycine [14].
  • This coupling is proposed to require a glutamate residue, E175 of bovine Hsc70, that is entirely conserved within the Hsp70 family, as it contacts bound Mg2+/ATP and is part of a hinge required for a postulated ATP-dependent opening/closing movement of the nucleotide binding cleft which then triggers substrate release [15].
  • Sucrose gradient centrifugation analysis followed by import assay showed that pOTC synthesized in rabbit reticulocyte lysate forms an import-competent complex of about 11S in an hsc70-dependent manner [12].

Physical interactions of HSPA8


Regulatory relationships of HSPA8

  • Auxilin also induced polymerization of Hsc70 and bound to the resulting polymer at a 1:1 molar ratio; here too the dissociation constant was 0.6 microM [17].
  • In Dex-treated cultures subjected to heat shock, hsc70 antisense RNA blocked the induction of hsp70, indicating that newly synthesized RNA was targeted effectively before it became translationally active [18].
  • Hsc70 suppressed eIF-2alpha phosphorylation and maintained the guanine nucleotide exchange activity of eIF-2B in heme-deficient RRL and in hemin-supplemented RRL exposed to elevated temperatures (42 degrees C), denatured protein (reduced carboxymethylated bovine serum albumin, RCM-BSA), oxidized glutathione or Hg2+ [19].

Other interactions of HSPA8

  • Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70 [20].
  • The Hsc70 molecular chaperone effects the uncoating reaction, and is guided to appropriate locations on clathrin lattices by the J-domain-containing co-chaperone molecule auxilin [21].
  • In contrast, NIVRKKK was a weaker stimulator of the Hsc70 ATPase activity compared with pigeon cytochrome c peptide and FYQLALT, a peptide optimized for binding to Hsc70 [2].
  • Furthermore, we investigated whether molecular chaperones with a proven role in protein folding and belonging to the other two major families of stress proteins, i.e. Hsp60 or Hsp90, can substitute for Hsc70 [22].
  • The dissociation constants of peptide P3a (the recognition sequence of clathrin light chain LCa by hsc70) and S peptide of ribonuclease for 60-kDa protein are 13 and 7 microM, respectively [1].

Analytical, diagnostic and therapeutic context of HSPA8


  1. Uncoupling of peptide-stimulated ATPase and clathrin-uncoating activity in deletion mutant of hsc70. Tsai, M.Y., Wang, C. J. Biol. Chem. (1994) [Pubmed]
  2. Hsc70-binding peptides selected from a phage display peptide library that resemble organellar targeting sequences. Takenaka, I.M., Leung, S.M., McAndrew, S.J., Brown, J.P., Hightower, L.E. J. Biol. Chem. (1995) [Pubmed]
  3. Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle. Höhfeld, J., Minami, Y., Hartl, F.U. Cell (1995) [Pubmed]
  4. Peptide binding and release by proteins implicated as catalysts of protein assembly. Flynn, G.C., Chappell, T.G., Rothman, J.E. Science (1989) [Pubmed]
  5. Uncoating of clathrin-coated vesicles in presynaptic terminals: roles for Hsc70 and auxilin. Morgan, J.R., Prasad, K., Jin, S., Augustine, G.J., Lafer, E.M. Neuron (2001) [Pubmed]
  6. Structural replacement of active site monovalent cations by the epsilon-amino group of lysine in the ATPase fragment of bovine Hsc70. Wilbanks, S.M., McKay, D.B. Biochemistry (1998) [Pubmed]
  7. Mapping the role of active site residues for transducing an ATP-induced conformational change in the bovine 70-kDa heat shock cognate protein. Johnson, E.R., McKay, D.B. Biochemistry (1999) [Pubmed]
  8. Mechanism of clathrin basket dissociation: separate functions of protein domains of the DnaJ homologue auxilin. Holstein, S.E., Ungewickell, H., Ungewickell, E. J. Cell Biol. (1996) [Pubmed]
  9. Stable clathrin: uncoating protein (hsc70) complexes in intact neurons and their axonal transport. Black, M.M., Chestnut, M.H., Pleasure, I.T., Keen, J.H. J. Neurosci. (1991) [Pubmed]
  10. Similarity of the three-dimensional structures of actin and the ATPase fragment of a 70-kDa heat shock cognate protein. Flaherty, K.M., McKay, D.B., Kabsch, W., Holmes, K.C. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  11. The 70-kDa heat shock protein chaperone nucleotide-binding domain in solution unveiled as a molecular machine that can reorient its functional subdomains. Zhang, Y., Zuiderweg, E.R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  12. The requirement of heat shock cognate 70 protein for mitochondrial import varies among precursor proteins and depends on precursor length. Terada, K., Ueda, I., Ohtsuka, K., Oda, T., Ichiyama, A., Mori, M. Mol. Cell. Biol. (1996) [Pubmed]
  13. Calf thymus Hsc70 protein protects and reactivates prokaryotic and eukaryotic enzymes. Ziemienowicz, A., Zylicz, M., Floth, C., Hübscher, U. J. Biol. Chem. (1995) [Pubmed]
  14. The hydroxyl of threonine 13 of the bovine 70-kDa heat shock cognate protein is essential for transducing the ATP-induced conformational change. Sousa, M.C., McKay, D.B. Biochemistry (1998) [Pubmed]
  15. The chaperone function of DnaK requires the coupling of ATPase activity with substrate binding through residue E171. Buchberger, A., Valencia, A., McMacken, R., Sander, C., Bukau, B. EMBO J. (1994) [Pubmed]
  16. The molecular chaperone Hsc70 assists the in vitro folding of the N-terminal nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator. Strickland, E., Qu, B.H., Millen, L., Thomas, P.J. J. Biol. Chem. (1997) [Pubmed]
  17. Interaction of auxilin with the molecular chaperone, Hsc70. Jiang, R.F., Greener, T., Barouch, W., Greene, L., Eisenberg, E. J. Biol. Chem. (1997) [Pubmed]
  18. Effects of dexamethasone, heat shock, and serum responses on the inhibition of Hsc70 synthesis by antisense RNA in NIH 3T3 cells. Li, T., Hightower, L.E. J. Cell. Physiol. (1995) [Pubmed]
  19. Evidence that Hsc70 negatively modulates the activation of the heme-regulated eIF-2alpha kinase in rabbit reticulocyte lysate. Thulasiraman, V., Xu, Z., Uma, S., Gu, Y., Chen, J.J., Matts, R.L. Eur. J. Biochem. (1998) [Pubmed]
  20. Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70. Bercovich, B., Stancovski, I., Mayer, A., Blumenfeld, N., Laszlo, A., Schwartz, A.L., Ciechanover, A. J. Biol. Chem. (1997) [Pubmed]
  21. Structure of an auxilin-bound clathrin coat and its implications for the mechanism of uncoating. Fotin, A., Cheng, Y., Grigorieff, N., Walz, T., Harrison, S.C., Kirchhausen, T. Nature (2004) [Pubmed]
  22. Hsc70, immunoglobulin heavy chain binding protein, and Hsp90 differ in their ability to stimulate transport of precursor proteins into mammalian microsomes. Wiech, H., Buchner, J., Zimmermann, M., Zimmermann, R., Jakob, U. J. Biol. Chem. (1993) [Pubmed]
  23. Visualization of the binding of Hsc70 ATPase to clathrin baskets: implications for an uncoating mechanism. Heymann, J.B., Iwasaki, K., Yim, Y.I., Cheng, N., Belnap, D.M., Greene, L.E., Eisenberg, E., Steven, A.C. J. Biol. Chem. (2005) [Pubmed]
  24. Conformational change of chaperone Hsc70 upon binding to a decapeptide: a circular dichroism study. Park, K., Flynn, G.C., Rothman, J.E., Fasman, G.D. Protein Sci. (1993) [Pubmed]
  25. Thermal activation of the bovine Hsc70 molecular chaperone at physiological temperatures: physical evidence of a molecular thermometer. Leung, S.M., Senisterra, G., Ritchie, K.P., Sadis, S.E., Lepock, J.R., Hightower, L.E. Cell Stress Chaperones (1996) [Pubmed]
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