A unique chaperoning mechanism in class A JDPs recognizes and stabilizes mutant p53

Mol Cell. 2024 Apr 18;84(8):1512-1526.e9. doi: 10.1016/j.molcel.2024.02.018. Epub 2024 Mar 19.


J-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity of and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here, we uncover a unique mechanism by which chaperones recognize misfolded clients, present in human class A JDPs. Through a newly identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class A JDP β-hairpin as a highly specific target for cancer therapeutics.

Keywords: J-domain proteins; NMR; molecular chaperones; p53; protein aggregation; protein misfolding.

MeSH terms

  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Neoplasms*
  • Protein Folding
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism


  • Tumor Suppressor Protein p53
  • Molecular Chaperones
  • HSP70 Heat-Shock Proteins