A client-binding site of Cdc37.
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.
Terasawa
Kazuya
K
Department of Biophysics and Biochemistry, and Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Science, University of Tokyo, Japan.
Minami
Yasufumi
Y
D000595:Amino Acid Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D018833:Chaperonins; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D025941:Protein Interaction Mapping; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism
C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D019908:Proto-Oncogene Proteins c-raf; D018833:Chaperonins