The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50cdc37
The mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50cdc37
复制标题
DOI：
10.1016/s0092-8674(03)01027-4
复制
发表时间：
2004-01-09
期刊：
影响因子：
64.5
通讯作者：
Pearl, LH
中科院分区：
文献类型：
--
作者：
Roe, SM;Ali, MMU;Pearl, LH
招募蛋白激酶客户的热休克蛋白90分子伴侣涉及cochaperone p50（cdc 37）作为一个支架，结合蛋白激酶通过其N-末端结构域和热休克蛋白90通过其C-末端区域。p50（cdc 37）也具有调节活性，在客户蛋白加载期间阻止Hsp 90的ATP酶循环。我们将p50（cdc 37）的结合位点定位于Hsp 90的N-末端核苷酸结合结构域，并确定了Hsp 90-p50（cdc 37）核心复合物的晶体结构。二聚体p50（cdc 37）结合到Hsp 90 N-结构域的表面，该表面涉及ATP依赖性N-末端二聚化并与伴侣蛋白的中间段结合。这种相互作用将盖片段固定在开放构象中，将精氨酸侧链插入ATP结合口袋中以使催化失效，并防止N结构域的反式激活相互作用。
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.