Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, U.S.A.
Rice University, Houston, Texas 77005, U.S.A.
Biochem Soc Trans. 2022 Dec 16;50(6):1725-1736. doi: 10.1042/BST20220590.
Hsp100 chaperones, also known as Clp proteins, constitute a family of ring-forming ATPases that differ in 3D structure and cellular function from other stress-inducible molecular chaperones. While the vast majority of ATP-dependent molecular chaperones promote the folding of either the nascent chain or a newly imported polypeptide to reach its native conformation, Hsp100 chaperones harness metabolic energy to perform the reverse and facilitate the unfolding of a misfolded polypeptide or protein aggregate. It is now known that inside cells and organelles, different Hsp100 members are involved in rescuing stress-damaged proteins from a previously aggregated state or in recycling polypeptides marked for degradation. Protein degradation is mediated by a barrel-shaped peptidase that physically associates with the Hsp100 hexamer to form a two-component system. Notable examples include the ClpA:ClpP (ClpAP) and ClpX:ClpP (ClpXP) proteases that resemble the ring-forming FtsH and Lon proteases, which unlike ClpAP and ClpXP, feature the ATP-binding and proteolytic domains in a single polypeptide chain. Recent advances in electron cryomicroscopy (cryoEM) together with single-molecule biophysical studies have now provided new mechanistic insight into the structure and function of this remarkable group of macromolecular machines.
Hsp100 伴侣蛋白，也称为 Clp 蛋白，构成了一个具有环形成 ATP 酶的家族，其 3D 结构和细胞功能与其他应激诱导的分子伴侣不同。虽然绝大多数依赖 ATP 的分子伴侣促进新生链或新导入的多肽折叠以达到其天然构象，但 Hsp100 伴侣蛋白利用代谢能量来进行相反的操作，促进错误折叠的多肽或蛋白质聚集体的解折叠。现在已知，在细胞和细胞器内，不同的 Hsp100 成员参与将应激损伤的蛋白质从先前的聚集状态中挽救出来，或者参与标记用于降解的多肽的回收。蛋白质降解是由一个桶形肽酶介导的，该酶与 Hsp100 六聚体物理结合形成一个两组件系统。值得注意的例子包括 ClpA:ClpP（ClpAP）和 ClpX:ClpP（ClpXP）蛋白酶，它们类似于形成环的 FtsH 和 Lon 蛋白酶，与 ClpAP 和 ClpXP 不同，它们的 ATP 结合和蛋白酶结构域在一条多肽链上。电子冷冻显微镜（cryoEM）和单分子生物物理研究的最新进展现在为这个非凡的大分子机器组的结构和功能提供了新的机制见解。
