Center for Quantitative Biology, School of Physics, Peking University, Beijing 100871, China.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02138, USA.
Biomolecules. 2020 Apr 18;10(4):629. doi: 10.3390/biom10040629.
Adenosine triphosphatases (ATPases) associated with a variety of cellular activities (AAA+), the hexameric ring-shaped motor complexes located in all ATP-driven proteolytic machines, are involved in many cellular processes. Powered by cycles of ATP binding and hydrolysis, conformational changes in AAA+ ATPases can generate mechanical work that unfolds a substrate protein inside the central axial channel of ATPase ring for degradation. Three-dimensional visualizations of several AAA+ ATPase complexes in the act of substrate processing for protein degradation have been resolved at the atomic level thanks to recent technical advances in cryogenic electron microscopy (cryo-EM). Here, we summarize the resulting advances in structural and biochemical studies of AAA+ proteases in the process of proteolysis reactions, with an emphasis on cryo-EM structural analyses of the 26S proteasome, Cdc48/p97 and FtsH-like mitochondrial proteases. These studies reveal three highly conserved patterns in the structure-function relationship of AAA+ ATPase hexamers that were observed in the human 26S proteasome, thus suggesting common dynamic models of mechanochemical coupling during force generation and substrate translocation.
三磷酸腺苷酶（ATPases）与多种细胞活动（AAA+）相关，是位于所有 ATP 驱动的蛋白水解机器中的六聚体环形马达复合物，参与许多细胞过程。在 AAA+ATP 酶的 ATP 结合和水解循环的驱动下，构象变化可以产生机械功，将底物蛋白在 ATP 酶环的中央轴向通道内展开进行降解。由于低温电子显微镜（cryo-EM）技术的最新进展，已经在原子水平上解析了几种 AAA+ATP 酶复合物在底物加工过程中的三维可视化，以进行蛋白降解。在这里，我们总结了在蛋白水解反应过程中 AAA+蛋白酶的结构和生化研究的最新进展，重点介绍了 26S 蛋白酶体、CDC48/p97 和 FtsH 样线粒体蛋白酶的 cryo-EM 结构分析。这些研究揭示了在人类 26S 蛋白酶体中观察到的 AAA+ATP 酶六聚体结构-功能关系中的三种高度保守模式，从而提出了在力产生和底物转位过程中机械化学偶联的共同动态模型。
