GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1

EMBO J. 1997 Oct 15;16(20):6209-16. doi: 10.1093/emboj/16.20.6209.


The BAG-1 protein appears to inhibit cell death by binding to Bcl-2, the Raf-1 protein kinase, and certain growth factor receptors, but the mechanism of inhibition remains enigmatic. BAG-1 also interacts with several steroid hormone receptors which require the molecular chaperones Hsc70 and Hsp90 for activation. Here we show that BAG-1 is a regulator of the Hsc70 chaperone. BAG-1 binds to the ATPase domain of Hsc70 and, in cooperation with Hsp40, stimulates Hsc70's steady-state ATP hydrolysis activity approximately 40-fold. Similar to the action of the GrpE protein on bacterial Hsp70, BAG-1 accelerates the release of ADP from Hsc70. Thus, BAG-1 regulates the Hsc70 ATPase in a manner contrary to the Hsc70-interacting protein Hip, which stabilizes the ADP-bound state. Intriguingly, BAG-1 and Hip compete in binding to the ATPase domain of Hsc70. Our results reveal an unexpected diversity in the regulation of Hsc70 and raise the possibility that the observed anti-apoptotic function of BAG-1 may be exerted through a modulation of the chaperone activity of Hsc70 on specific protein folding and maturation pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphate / metabolism
  • Apoptosis / physiology*
  • Carrier Proteins / isolation & purification
  • Carrier Proteins / metabolism*
  • DNA-Binding Proteins
  • HSC70 Heat-Shock Proteins
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Models, Biological
  • Molecular Chaperones / metabolism
  • Protein Binding
  • Transcription Factors


  • BCL2-associated athanogene 1 protein
  • Carrier Proteins
  • DNA-Binding Proteins
  • DNAJB1 protein, human
  • GRPEL1 protein, human
  • GrpE-like 1 mitochondrial protein, vertebrate
  • HSC70 Heat-Shock Proteins
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • HSPA8 protein, human
  • Heat-Shock Proteins
  • Hip chaperone
  • Molecular Chaperones
  • Transcription Factors
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Adenosine Triphosphatases