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

Douglas E Feldman1, Christoph Spiess, Daniel E Howard

  • 1Department of Biological Sciences and BioX Program, Stanford University, E200A James Clark Center, 318 Campus Drive, Stanford, CA 94305, USA.

Molecular Cell
|November 26, 2003
PubMed

Insights

The study identifies specific VHL protein structures that bind to the TRiC/CCT chaperone, crucial for proper protein folding. Mutations disrupting this binding cause misfolding and disease, highlighting a new class of cancer-causing mutations.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Background:

  • The TRiC/CCT chaperonin is essential for folding specific proteins in eukaryotes.
  • The Von Hippel-Lindau (VHL) tumor suppressor protein requires TRiC/CCT for correct folding.
  • Protein misfolding is linked to various diseases, including cancer.

Purpose of the Study:

  • To elucidate the molecular determinants of VHL binding to TRiC/CCT.
  • To investigate how disease-causing mutations in VHL affect chaperonin interaction and protein folding.
  • To understand the role of TRiC/CCT specificity in folding aggregation-prone proteins.

Main Methods:

  • Analysis of VHL protein structure and mutations.
  • In vitro and in vivo protein folding assays.
  • Chaperonin binding studies.

Main Results:

  • Two hydrophobic beta strands in VHL specify TRiC/CCT binding.
  • Tumor-associated VHL mutations disrupt these binding sites, leading to misfolding.
  • Some misfolded VHL mutants can refold independently of chaperonins.
  • TRiC/CCT specificity for beta strands may aid in folding aggregation-prone polypeptides.

Conclusions:

  • Identified specific VHL structural elements critical for TRiC/CCT chaperonin interaction.
  • Demonstrated that mutations disrupting chaperonin binding cause VHL misfolding and disease.
  • Revealed a mechanism where disease arises from impaired chaperone-mediated folding in vivo.

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