Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37.
Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37.
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DOI：
10.1016/j.molcel.2016.04.005
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发表时间：
2016-04-21
期刊：
影响因子：
16
通讯作者：
Gelis I
中科院分区：
文献类型：
--
作者：
Keramisanou D;Aboalroub A;Zhang Z;Liu W;Marshall D;Diviney A;Larsen RW;Landgraf R;Gelis I
尽管Hsp90具有重要的功能，但人们对控制底物进入其伴侣循环的机制知之甚少。我们发现，CDC37辅伴侣的作用超出了接头蛋白的范围，并发现它只参与客户激酶的选择性招募。CDC37识别客户和非客户中的激酶特异性决定因素，并作为一种通用的激酶扫描因子。在客户-非客户连续体中，激酶的分选依赖于CDC37通过局部展开客户来挑战客户构象稳定性的能力。这种亚稳构象状态对Cdc37具有很高的亲和力，并通过多结构域协伴侣界面形成稳定的络合物。与非客户的相互作用不伴随底物的构象变化，导致底物解离。总的来说，CDC37执行蛋白激酶的质量控制，其中诱导的构象不稳定性作为Hsp90依赖和稳定的辅伴侣结合的“旗帜”。
Despite the essential functions of Hsp90, little is known about the mechanism that controls substrate entry into its chaperone cycle. We show that the role of Cdc37 cochaperone reaches beyond that of an adaptor protein and find that it participates in the selective recruitment of only client kinases. Cdc37 recognizes kinase specificity determinants in both clients and nonclients and acts as a general kinase scanning factor. Kinase sorting within the client-to-nonclient continuum relies on the ability of Cdc37 to challenge the conformational stability of clients by locally unfolding them. This metastable conformational state has high affinity for Cdc37 and forms stable complexes through a multidomain cochaperone interface. The interaction with nonclients is not accompanied by conformational changes of the substrate and results in substrate dissociation. Collectively, Cdc37 performs a quality control of protein kinases, where induced conformational instability acts as a “flag” for Hsp90 dependence and stable cochaperone association.