Howard Hughes Medical Institute (HHMI) and the Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Science. 2016 Jun 24;352(6293):1542-7. doi: 10.1126/science.aaf5023.
The Hsp90 molecular chaperone and its Cdc37 cochaperone help stabilize and activate more than half of the human kinome. However, both the mechanism by which these chaperones assist their "client" kinases and the reason why some kinases are addicted to Hsp90 while closely related family members are independent are unknown. Our structural understanding of these interactions is lacking, as no full-length structures of human Hsp90, Cdc37, or either of these proteins with a kinase have been elucidated. Here we report a 3.9 angstrom cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex. Surprisingly, the two lobes of Cdk4 are completely separated with the β4-β5 sheet unfolded. Cdc37 mimics part of the kinase N lobe, stabilizing an open kinase conformation by wedging itself between the two lobes. Finally, Hsp90 clamps around the unfolded kinase β5 strand and interacts with exposed N- and C-lobe interfaces, protecting the kinase in a trapped unfolded state. On the basis of this structure and an extensive amount of previously collected data, we propose unifying conceptual and mechanistic models of chaperone-kinase interactions.
热休克蛋白 90（Hsp90）分子伴侣及其共伴侣 Cdc37 有助于稳定和激活超过一半的人类激酶组。然而，这些伴侣协助其“客户”激酶的机制以及某些激酶对 Hsp90 上瘾而密切相关的家族成员却不依赖于 Hsp90 的原因尚不清楚。由于尚未阐明全长人 Hsp90、Cdc37 或这两种蛋白质与激酶的结构，因此我们对这些相互作用的结构理解还很缺乏。在这里，我们报告了 Hsp90-Cdc37-Cdk4 激酶复合物的 3.9 埃冷冻电镜结构。令人惊讶的是，Cdk4 的两个叶完全分离，β4-β5 片层展开。Cdc37 模拟激酶 N lobe 的一部分，通过楔入两个叶之间，稳定了开放的激酶构象。最后，Hsp90 围绕展开的激酶β5 链夹住，并与暴露的 N 和 C lobe 界面相互作用，将激酶保护在被困的展开状态下。基于该结构和之前收集的大量数据，我们提出了统一的伴侣-激酶相互作用的概念和机制模型。
