Department of Pharmaceutical Chemistry and The Institute for Neurodegenerative Disease , University of California-San Francisco , San Francisco , California 94158 , United States.
Acc Chem Res. 2018 Apr 17;51(4):940-949. doi: 10.1021/acs.accounts.8b00036. Epub 2018 Apr 3.
Molecular chaperones play a central role in protein homeostasis (a.k.a. proteostasis) by balancing protein folding, quality control, and turnover. To perform these diverse tasks, chaperones need the malleability to bind nearly any "client" protein and the fidelity to detect when it is misfolded. Remarkably, these activities are carried out by only ∼180 dedicated chaperones in humans. How do a relatively small number of chaperones maintain cellular and organismal proteostasis for an entire proteome? Furthermore, once a chaperone binds a client, how does it "decide" what to do with it? One clue comes from observations that individual chaperones engage in protein-protein interactions (PPIs)-both with each other and with their clients. These physical links coordinate multiple chaperones into organized, functional complexes and facilitate the "handoff" of clients between them. PPIs also link chaperones and their clients to other cellular pathways, such as those that mediate trafficking (e.g., cytoskeleton) and degradation (e.g., proteasome). The PPIs of the chaperone network have a wide range of affinity values (nanomolar to micromolar) and involve many distinct types of domain modules, such as J domains, zinc fingers, and tetratricopeptide repeats. Many of these motifs have the same binding surfaces on shared partners, such that members of one chaperone class often compete for the same interactions. Somehow, this collection of PPIs draws together chaperone families and creates multiprotein subnetworks that are able to make the "decisions" of protein quality control. The key to understanding chaperone-mediated proteostasis might be to understand how PPIs are regulated. This Account will discuss the efforts of our group and others to map, measure, and chemically perturb the PPIs within the molecular chaperone network. Structural biology methods, including X-ray crystallography, NMR spectroscopy, and electron microscopy, have all played important roles in visualizing the chaperone PPIs. Guided by these efforts and -omics approaches to measure PPIs, new advances in high-throughput chemical screening that are specially designed to account for the challenges of this system have emerged. Indeed, chemical biology has played a particularly important role in this effort, as molecules that either promote or inhibit specific PPIs have proven to be invaluable research probes in cells and animals. In addition, these molecules have provided leads for the potential treatment of protein misfolding diseases. One of the major products of this research field has been the identification of putative PPI drug targets within the chaperone network, which might be used to change chaperone "decisions" and rebalance proteostasis.
分子伴侣在蛋白质动态平衡（又称蛋白质稳态）中发挥核心作用，通过平衡蛋白质折叠、质量控制和周转。为了执行这些不同的任务，伴侣需要有可塑性来结合几乎任何“客户”蛋白质，并具有检测其错误折叠的保真度。值得注意的是，人类中只有约 180 种专门的伴侣来执行这些活动。相对较少的伴侣如何维持整个蛋白质组的细胞和生物体的蛋白质动态平衡？此外，一旦伴侣结合了客户，它如何“决定”如何处理它？一个线索来自于观察到单个伴侣参与蛋白质-蛋白质相互作用（PPIs）-彼此之间以及与它们的客户。这些物理联系将多个伴侣协调到有组织的、功能性的复合物中，并促进它们之间的“客户”传递。PPIs 还将伴侣及其客户与其他细胞途径（如介导运输的途径（例如，细胞骨架）和降解途径（例如，蛋白酶体））联系起来。伴侣网络的 PPIs 具有广泛的亲和力值（纳摩尔到微摩尔），并涉及许多不同类型的结构域模块，如 J 结构域、锌指和四肽重复。这些基序中的许多在共享伴侣上具有相同的结合表面，使得一个伴侣家族的成员经常争夺相同的相互作用。不知何故，这些 PPIs 的集合将伴侣家族聚集在一起，并创建能够做出蛋白质质量控制“决策”的多蛋白子网。理解伴侣介导的蛋白质动态平衡的关键可能是理解 PPIs 是如何调节的。本账户将讨论我们小组和其他小组的努力，以绘制、测量和化学扰动分子伴侣网络内的 PPIs。包括 X 射线晶体学、NMR 光谱学和电子显微镜在内的结构生物学方法都在可视化伴侣 PPIs 方面发挥了重要作用。在这些努力和测量 PPIs 的组学方法的指导下，出现了专门设计用于解决该系统挑战的高通量化学筛选的新进展。事实上，化学生物学在这方面发挥了特别重要的作用，因为促进或抑制特定 PPIs 的分子已被证明是细胞和动物中非常宝贵的研究探针。此外，这些分子为蛋白质错误折叠疾病的潜在治疗提供了线索。该研究领域的主要成果之一是在伴侣网络中确定了潜在的 PPI 药物靶点，这些靶点可用于改变伴侣“决策”并重新平衡蛋白质动态平衡。
