The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50cdc37

被引:275
作者
Roe, SM
Ali, MMU
Meyer, P
Vaughan, CK
Panaretou, B
Piper, PW
Prodromou, C
Pearl, LH
机构
[1] Inst Canc Res, Sect Struct Biol, Chester Beatty Labs, London SW3 6JB, England
[2] Kings Coll London, Div Life Sci, London SE1 9NN, England
[3] UCL, Dept Biochem & Mol Biol, London WC1E 6BT, England
基金
英国惠康基金; 英国医学研究理事会;
关键词
D O I
10.1016/S0092-8674(03)01027-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:87 / 98
页数:12
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