A client-binding site of Cdc37

FEBS J. 2005 Sep;272(18):4684-90. doi: 10.1111/j.1742-4658.2005.04884.x.

Abstract

The molecular chaperone Hsp90 is distinct from Hsp70 and chaperonin in that client proteins are apparently restricted to a subset of proteins categorized as cellular signaling molecules. Among these, many specific protein kinases require the assistance of Hsp90 and its co-chaperone Cdc37/p50 for their biogenesis. A series of Cdc37 deletion mutants revealed that all mutants capable of binding Raf-1 possess amino acid residues between 181 and 200. The 20-residue region is sufficient and, in particular, a five-residue segment (residue 191-195) is essential for binding to Raf-1. These five residues are present in one alpha helix (residues 184-199) in the middle of Cdc37, which is unexpectedly nested within the Hsp90-interacting domain of Cdc37, which was recently determined by crystallography, but does not seem to contribute to direct contact with Hsp90. Furthermore, an N-terminally truncated mutant of Cdc37 composed of residues 181-378 was shown to bind the N-terminal portion of Raf-1 (subdomains I-IV). This mutant can bind not only other Hsp90 client protein kinases, Akt1, Aurora B and Cdk4, but also Cdc2 and Cdk2, which to date have not been shown to physically interact with Cdc37. These results suggest that a region of Cdc37 other than the client-binding site may be responsible for discriminating client protein kinases from others.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Chaperonins
  • HSP90 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Humans
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Peptide Fragments / metabolism
  • Protein Interaction Mapping*
  • Proto-Oncogene Proteins c-raf / metabolism

Substances

  • CDC37 protein, human
  • Cell Cycle Proteins
  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones
  • Peptide Fragments
  • Proto-Oncogene Proteins c-raf
  • Chaperonins