The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37)

Roe, S Mark, Ali, Maruf M U, Meyer, Philippe, Vaughan, Cara K, Panaretou, Barry, Piper, Peter W, Prodromou, Chrisostomos and Pearl, Laurence H (2004) The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Cell, 116 (1). pp. 87-98. ISSN 0092-8674

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Abstract

Recruitment of protein kinase clients to the Hsp90 chaperone involves the cochaperone p50(cdc37) acting as a scaffold, binding protein kinases via its N-terminal domain and Hsp90 via its C-terminal region. p50(cdc37) also has a regulatory activity, arresting Hsp90's ATPase cycle during client-protein loading. We have localized the binding site for p50(cdc37) to the N-terminal nucleotide binding domain of Hsp90 and determined the crystal structure of the Hsp90-p50(cdc37) core complex. Dimeric p50(cdc37) binds to surfaces of the Hsp90 N-domain implicated in ATP-dependent N-terminal dimerization and association with the middle segment of the chaperone. This interaction fixes the lid segment in an open conformation, inserts an arginine side chain into the ATP binding pocket to disable catalysis, and prevents trans-activating interaction of the N domains.

Item Type: Article
Keywords: Adenosine Triphosphate/metabolism Arginine/metabolism Binding Sites/physiology Cell Cycle Proteins/*metabolism Dimerization *Drosophila Proteins HSP90 Heat-Shock Proteins/*metabolism Models, Molecular Molecular Chaperones/*metabolism Molecular Sequence Data Molecular Structure Protein Binding/physiology Protein Conformation Protein Kinases/*metabolism Protein Structure, Tertiary/physiology Sequence Homology, Amino Acid
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Chrisostomos Prodromou
Date Deposited: 25 Feb 2015 09:29
Last Modified: 25 Feb 2015 09:29
URI: http://sro.sussex.ac.uk/id/eprint/44371
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