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Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding.

The eukaryotic chaperonin TRiC/CCT mediates folding of an essential subset of newly synthesized proteins, including the tumor suppressor VHL. Here we show that chaperonin binding is specified by two short hydrophobic beta strands in VHL that, upon folding, become buried within the native structure. These TRiC binding determinants are disrupted by tumor-causing point mutations that interfere with chaperonin association and lead to misfolding. Strikingly, while unable to fold correctly in vivo, some of these VHL mutants can reach the native state when refolded in a chaperonin-independent manner. The specificity of TRiC/CCT for extended hydrophobic beta strands may help explain its role in folding aggregation-prone polypeptides. Our findings reveal a class of disease-causing mutations that inactivate protein function by disrupting chaperone-mediated folding in vivo.

Pubmed ID: 14636579


  • Feldman DE
  • Spiess C
  • Howard DE
  • Frydman J


Molecular cell

Publication Data

November 25, 2003

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM56433

Mesh Terms

  • Animals
  • Cattle
  • Cell Line
  • Chaperonins
  • HSP70 Heat-Shock Proteins
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Microtubule-Associated Proteins
  • Models, Molecular
  • Neoplasms
  • Nuclear Proteins
  • Point Mutation
  • Protein Binding
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • t-Complex Genome Region