Protein-Protein Interactions in the Molecular Chaperone Network.
Protein-Protein Interactions in the Molecular Chaperone Network.
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DOI：
10.1021/acs.accounts.8b00036
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发表时间：
2018-04-17
影响因子：
18.3
通讯作者：
Gestwicki JE
中科院分区：
文献类型：
--
作者：
Freilich R;Arhar T;Abrams JL;Gestwicki JE
结论分子伴侣在蛋白质稳态中起着重要作用。通过平衡蛋白质折叠、质量控制和周转（turnover）实现蛋白质稳态。为了完成这些不同的任务，分子伴侣需要具有与几乎任何“客户”蛋白质结合的延展性，以及检测错误折叠时的保真度。值得注意的是，这些活动在人类中仅由大约180个专用的伴侣进行。相对少量的分子伴侣是如何维持整个蛋白质组的细胞和生物体蛋白质稳定的？此外，一旦监护人绑定了客户，它如何“决定”如何处理它？一个线索来自于观察到个体伴侣参与蛋白质-蛋白质相互作用（PPI）-彼此之间以及与客户之间。这些物理链接将多个伴侣协调成有组织的功能复合体，并促进客户端在它们之间的“切换”。PPI还将分子伴侣及其客户与其他细胞途径联系起来，例如介导贩运的那些途径（例如，细胞骨架）和降解（例如，蛋白酶体）。分子伴侣网络的PPI具有广泛的亲和力值（纳摩尔至微摩尔），并涉及许多不同类型的结构域模块，如J结构域、锌指和三肽重复序列。这些基序中的许多基序在共享的伴侣上具有相同的结合表面，使得一个分子伴侣类别的成员经常竞争相同的相互作用。不知何故，这些PPI集合将分子伴侣家族聚集在一起，并创建了能够做出蛋白质质量控制“决定”的多蛋白质子网络。了解分子伴侣介导的蛋白质稳定的关键可能是了解PPI是如何被调节的。这个账户将讨论我们小组和其他人在分子伴侣网络中绘制，测量和化学干扰PPI的努力。结构生物学方法，包括X射线晶体学，核磁共振光谱学和电子显微镜，都发挥了重要作用，在可视化的伴侣蛋白PPI。在这些努力和测量PPI的组学方法的指导下，出现了专门设计用于应对该系统挑战的高通量化学筛选的新进展。事实上，化学生物学在这一努力中发挥了特别重要的作用，因为促进或抑制特定PPI的分子已被证明是细胞和动物中宝贵的研究探针。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。这一研究领域的主要成果之一是确定了分子伴侣网络中的假定PPI药物靶点，这可能用于改变分子伴侣的“决定”和重新平衡蛋白质稳态。
ConspectusMolecular 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.
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影响因子：
16.8
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4
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Chafekar, Sidhartha M.;Wisen, Susanne;Thompson, Andrea D.;Echeverria, AnaLisa;Walter, Gladis M.;Evans, Christopher G.;Makley, Leah N.;Gestwicki, Jason E.;Duennwald, Martin L.
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Duennwald, Martin L.
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Vierling, E
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通讯作者：
Gestwicki JE
影响因子：
56.9
作者：
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通讯作者：
Kuriyan, J