Coordinated Conformational Processing of the Tumor Suppressor Protein p53 by the Hsp70 and Hsp90 Chaperone Machineries

Mol Cell. 2019 May 16;74(4):816-830.e7. doi: 10.1016/j.molcel.2019.03.026. Epub 2019 Apr 23.


p53, the guardian of the genome, requires chaperoning by Hsp70 and Hsp90. However, how the two chaperone machineries affect p53 conformation and regulate its function remains elusive. We found that Hsp70, together with Hsp40, unfolds p53 in an ATP-dependent reaction. This unfolded state of p53 is susceptible to aggregation after release induced by the nucleotide exchange factor Bag-1. However, when Hsp90 and the adaptor protein Hop are present, p53 is transferred from Hsp70 to Hsp90, allowing restoration of the native state upon ATP hydrolysis. Our results suggest that the p53 conformation is constantly remodeled by the two major chaperone machineries. This connects p53 activity to stress, and the levels of free molecular chaperones are important factors regulating p53 activity. Together, our findings reveal an intricate interplay and cooperation of Hsp70 and Hsp90 in regulating the conformation of a client.

Keywords: ATPase activity; DNA binding activity; Hsp70; Hsp90; chaperone interactions; co-chaperones; conformational dynamics; p53; protein folding; spFRET.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • HSP70 Heat-Shock Proteins / chemistry*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / chemistry*
  • HSP90 Heat-Shock Proteins / genetics
  • Humans
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / genetics
  • Protein Aggregates / genetics
  • Protein Binding / genetics
  • Protein Conformation*
  • Protein Folding
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics


  • BCL2-associated athanogene 1 protein
  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones
  • Protein Aggregates
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Adenosine Triphosphate