The chaperone proteins HSP70, HSP40/DnaJ and GRP78/BiP suppress misfolding and formation of β-sheet-containing aggregates by human amylin: a potential role for defective chaperone biology in Type 2 diabetes

Biochem J. 2010 Nov 15;432(1):113-21. doi: 10.1042/BJ20100434.


Misfolding of the islet β-cell peptide hA (human amylin) into β-sheet-containing oligomers is linked to β-cell apoptosis and the pathogenesis of T2DM (Type 2 diabetes mellitus). In the present study, we have investigated the possible effects on hA misfolding of the chaperones HSP (heat-shock protein) 70, GRP78/BiP (glucose-regulated protein of 78 kDa/immunoglobulin heavy-chain-binding protein) and HSP40/DnaJ. We demonstrate that hA underwent spontaneous time-dependent β-sheet formation and aggregation by thioflavin-T fluorescence in solution, whereas rA (rat amylin) did not. HSP70, GRP78/BiP and HSP40/DnaJ each independently suppressed hA misfolding. Maximal molar protein/hA ratios at which chaperone activity was detected were 1:200 (HSP70, HSP40/DnaJ and GRP78/BiP). By contrast, none of the chaperones modified the secondary structure of rA. hA, but not rA, was co-precipitated independently with HSP70 and GRP78/BiP by anti-amylin antibodies. As these effects occur at molar ratios consistent with chaperone binding to relatively rare misfolded hA species, we conclude that HSP70 and GRP78/BiP can detect and bind misfolded hA oligomers, thereby effectively protecting hA against bulk misfolding and irreversible aggregation. Defective β-cell chaperone biology could contribute to hA misfolding and initiation of apoptosis in T2DM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Circular Dichroism
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Endoplasmic Reticulum Chaperone BiP
  • HSP40 Heat-Shock Proteins / metabolism*
  • HSP70 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Immunoprecipitation
  • Islet Amyloid Polypeptide / chemistry*
  • Islet Amyloid Polypeptide / metabolism
  • Molecular Chaperones / metabolism
  • Molecular Chaperones / physiology
  • Protein Binding
  • Protein Folding
  • Protein Structure, Secondary
  • Rats
  • Solutions


  • Endoplasmic Reticulum Chaperone BiP
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Islet Amyloid Polypeptide
  • Molecular Chaperones
  • Solutions