Function, Therapeutic Potential, and Inhibition of Hsp70 Chaperones
Function, Therapeutic Potential, and Inhibition of Hsp70 Chaperones
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DOI：
10.1021/acs.jmedchem.0c02091
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发表时间：
2021-05-19
影响因子：
7.3
通讯作者：
Chapman, Eli
中科院分区：
文献类型：
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作者：
Ambrose, Andrew J.;Chapman, Eli
Hsp70是所有生物中最高度保守的蛋白质之一。通过客户蛋白上暴露的疏水残基的反复结合和释放，Hsp70可以防止聚集并促进折叠到其客户蛋白的天然状态。人类蛋白质组包含8个典型的Hsp70。由于Hsp70相对混杂，它们在折叠大部分蛋白质组中发挥作用。Hsp70通过其调节蛋白质稳态的能力与疾病有关。近年来，研究人员试图开发Hsp70亚型的选择性抑制剂，以更好地了解单个亚型在生物学中的作用和潜在的治疗方法。选择性抑制剂来自于合理设计、强制定位和偶然发现，但完全选择性抑制剂的开发仍然难以捉摸。在本综述中，我们讨论了热休克蛋白70的结构和功能，已知的热休克蛋白70的客户端蛋白，热休克蛋白70在疾病中的作用，以及目前的努力，发现热休克蛋白70调节剂。
Hsp70s are among the most highly conserved proteins in all of biology. Through an iterative binding and release of exposed hydrophobic residues on client proteins, Hsp70s can prevent aggregation and promote folding to the native state of their client proteins. The human proteome contains eight canonical Hsp70s. Because Hsp70s are relatively promiscuous they play a role in folding a large proportion of the proteome. Hsp70s are implicated in disease through their ability to regulate protein homeostasis. In recent years, researchers have attempted to develop selective inhibitors of Hsp70 isoforms to better understand the role of individual isoforms in biology and as potential therapeutics. Selective inhibitors have come from rational design, forced localization, and serendipity, but the development of completely selective inhibitors remains elusive. In the present review, we discuss the Hsp70 structure and function, the known Hsp70 client proteins, the role of Hsp70s in disease, and current efforts to discover Hsp70 modulators.