PDF(Pubmed)
Abstract：
The Heat Shock Protein 90 (Hsp90) molecular chaperone is a key driver of protein homeostasis (proteostasis) under physiologically normal and stress conditions. In eukaryotes, Hsp90 is essential and is one of the most abundant proteins in a cell where the chaperone shuttles between the cytoplasm and nucleus to fold, stabilize, and regulate client proteins and protein complexes. Numerous high-throughput screens have mapped the Hsp90 interactome, building a vast network comprising ∼25% of the proteome in budding yeast. How Hsp90 is able to associate with this diverse and large cadre of targets is critical to comprehending how the proteostatic process works. Here, we review recent progress on our understanding of the molecular underpinnings driving Hsp90-client interactions from both the perspective of the targets and Hsp90. In addition to considering the available Hsp90-client structures, we also assessed recently identified Hsp90-client peptide complexes to build a model that justifies how Hsp90 might recognize a wide spectrum of target proteins. In brief, Hsp90 either directly recognizes a site within an intrinsically disordered region (IDR) of a client protein to transiently regulate that client or it associates with an unstructured polypeptide section created by the concerted efforts of multiple chaperones and cochaperones to stably associate with a client. Overall, Hsp90 exploits a common recognition property (i.e., IDR) within diverse clients to support chaperone-actionthereby enabling its central role in proteostasis.
摘要：
热休克蛋白90（Hsp90）分子伴侣是生理正常和应激条件下蛋白质稳态（蛋白质稳态）的关键驱动因素。在真核生物中,Hsp90是必需的，是细胞中最丰富的蛋白质之一，伴侣在细胞质和细胞核之间穿梭以折叠，稳定,并调节客户蛋白质和蛋白质复合物。许多高通量屏幕已经映射了Hsp90相互作用组，建立一个庞大的网络，包括25%的出芽酵母蛋白质组。Hsp90如何能够与这种多样化和庞大的目标联系起来，对于理解蛋白质抑制过程的工作方式至关重要。这里,我们从靶标和Hsp90的角度回顾了我们对驱动Hsp90-客户端相互作用的分子基础的理解的最新进展。除了考虑可用的Hsp90客户端结构，我们还评估了最近鉴定的Hsp90-客户端肽复合物,以建立一个模型,证明Hsp90如何识别广谱的靶蛋白.简而言之,Hsp90直接识别客户蛋白的固有无序区域(IDR)内的位点以瞬时调节该客户,或者它与由多个伴侣和共伴侣的协同努力产生的非结构化多肽区段相关联以稳定地与客户相关联。总的来说,Hsp90利用了一个共同的识别属性(即，IDR）在不同的客户中支持伴侣行为，从而使其在蛋白质稳定中发挥核心作用。
