Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System.
Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System.
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DOI：
10.1016/j.celrep.2017.10.042
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发表时间：
2017-10-31
期刊：
影响因子：
8.8
通讯作者：
Endicott JA
中科院分区：
文献类型：
--
作者：
Hallett ST;Pastok MW;Morgan RML;Wittner A;Blundell KLIM;Felletar I;Wedge SR;Prodromou C;Noble MEM;Pearl LH;Endicott JA
选择性招募蛋白激酶的热休克蛋白90系统介导的衔接子共伴侣Cdc 37。我们发现，CDK 4和CDK 6组装成蛋白质复合物是由Cdc 37-Hsp 90系统差异调节。与其他Hsp 90激酶客户一样，CDK 4/6与Cdc 37的结合被ATP竞争性抑制剂阻断。Cdc 37-Hsp 90将CDK 6放弃给D3型和病毒型细胞周期蛋白以及INK家族CDK抑制剂，而CDK 4放弃给INK，但不太容易放弃给细胞周期蛋白。p21 CIP 1和p27 KIP 1 CDK抑制剂在从Cdc 37置换CDK 4和CDK 6方面不如INK有效。然而，它们与D型细胞周期蛋白合作产生含有CDK 4/6的三元复合物，该三元复合物抵抗由Cdc 37引起的细胞周期蛋白D置换，这表明了解释归因于CIP/KIP家族成员的组装因子活性的分子机制。总之，我们的数据揭示了多种机制，Hsp 90系统可以控制CDK 4和CDK 6-细胞周期蛋白复合物在不同的细胞条件下形成。CDK抑制剂和D型细胞周期蛋白竞争性地从Cdc 37-Hsp 90中分离CDK 4/6 ATP竞争性抑制剂的结合导致CDK 4/6从Cdc 37-Hsp 90中置换。重组CDK 4/6客户激酶从Cdc 37-Hsp 90到CDK调节伙伴的移交，并提出CIP/KIP CDK抑制剂的组装因子活性的模型。他们发现，临床使用的CDK 4/6抑制剂可以在亚微摩尔浓度下从Cdc 37-Hsp 90分子伴侣系统中取代G1 CDKs。
Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions. CDK inhibitors and D-type cyclins competitively sequester CDK4/6 from Cdc37-Hsp90 Binding of ATP-competitive inhibitors causes CDK4/6 to be displaced from Cdc37-Hsp90 Cancer-associated p16INK4a mutants distinguish CDK4 and CDK6 A model for the assembly factor activity of CIP/KIP CDK inhibitors is proposed Hallett et al. reconstitute CDK4/6 client kinase handover from Cdc37-Hsp90 to CDK regulatory partners and propose a model for the assembly factor activity of CIP/KIP CDK inhibitors. They find that CDK4/6 inhibitors in clinical use can displace G1 CDKs from the Cdc37-Hsp90 chaperone system at submicromolar concentrations.
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