Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Cell. 2012 Aug 31;150(5):987-1001. doi: 10.1016/j.cell.2012.06.047.
HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family.
HSP90 是一种分子伴侣，它与许多称为客户的底物蛋白结合。它在人类生物学和医学中发挥着许多重要作用，但 HSP90 识别客户的决定因素仍然令人沮丧地难以捉摸。我们系统地和定量地调查了大多数人类激酶、转录因子和 E3 连接酶与 HSP90 及其共伴侣 CDC37 的相互作用。出乎意料的是，与转录因子相比，更多的激酶与 HSP90 结合。CDC37 与激酶相互作用，但与转录因子或 E3 连接酶不相互作用。HSP90::kinase 相互作用在 100 倍的范围内连续变化，为研究客户蛋白识别提供了一个平台。在野生型客户中，HSP90 不结合特定的序列基序，而是与内在不稳定的激酶结合。用各种小分子稳定激酶的活性或非活性构象会降低 HSP90 的结合。我们的结果确立了 HSP90 客户识别作为一个组合过程：CDC37 提供对激酶家族的识别，而热力学参数则决定了家族内的客户结合。
