title: The Cdc37 protein kinase-binding domain is sufficient for protein kinase activity and cell viability.
abstract: Cdc37 is a molecular chaperone required for folding of protein kinases. It functions in association with Hsp90, although little is known of its mechanism of action or where it fits into a folding pathway involving other Hsp90 cochaperones. Using a genetic approach with Saccharomyces cerevisiae, we show that CDC37 overexpression suppressed a defect in v-Src folding in yeast deleted for STI1, which recruits Hsp90 to misfolded clients. Expression of CDC37 truncation mutants that were deleted for the Hsp90-binding site stabilized v-Src and led to some folding in both sti1Delta and hsc82Delta strains. The protein kinase-binding domain of Cdc37 was sufficient for yeast cell viability and permitted efficient signaling through the yeast MAP kinase-signaling pathway. We propose a model in which Cdc37 can function independently of Hsp90, although its ability to do so is restricted by its normally low expression levels. This may be a form of regulation by which cells restrict access to Cdc37 until it has passed through a triage involving other chaperones such as Hsp70 and Hsp90.
authors.affiliation: Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Lee
authors.forename: Jie
authors.initials: J
authors.lastname: Rao
authors.forename: Albert
authors.initials: A
authors.lastname: Fliss
authors.forename: Emy
authors.initials: E
authors.lastname: Yang
authors.forename: Stephen
authors.initials: S
authors.lastname: Garrett
authors.forename: Avrom J
authors.initials: AJ
authors.lastname: Caplan
mesh_terms: D001665:Binding Sites; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D029721:Drosophila Proteins; D005816:Genetic Complementation Test; D005982:Glutathione Transferase / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D013696:Temperature
chemical_list: C513270:CDC37 protein, S cerevisiae; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src)