Translocases of the AAA+ (ATPases Associated with various cellular Activities) family are powerful molecular machines that use the mechano-chemical coupling of ATP hydrolysis and conformational changes to thread DNA or protein substrates through their central channel for many important biological processes. These motors comprise hexameric rings of ATPase subunits, in which highly conserved nucleotide-binding domains form active-site pockets near the subunit interfaces and aromatic pore-loop residues extend into the central channel for substrate binding and mechanical pulling. Over the past 2 years, 41 cryo-EM structures have been solved for substrate-bound AAA+ translocases that revealed spiral-staircase arrangements of pore-loop residues surrounding substrate polypeptides and indicating a conserved hand-over-hand mechanism for translocation. The subunits' vertical positions within the spiral arrangements appear to be correlated with their nucleotide states, progressing from ATP-bound at the top to ADP or apo states at the bottom. Studies describing multiple conformations for a particular motor illustrate the potential coupling between ATP-hydrolysis steps and subunit movements to propel the substrate. Experiments with double-ring, Type II AAA+ motors revealed an offset of hydrolysis steps between the two ATPase domains of individual subunits, and the upper ATPase domains lacking aromatic pore loops frequently form planar rings. This review summarizes the critical advances provided by recent studies to our structural and functional understanding of hexameric AAA+ translocases, as well as the important outstanding questions regarding the underlying mechanisms for coordinated ATP-hydrolysis and mechano-chemical coupling.

中文翻译：

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易位的阶梯：AAA +运动结构揭示了ATP依赖的底物易位的机制。

AAA +（与各种细胞活动相关的ATPases）家族的转位酶是功能强大的分子机器，利用ATP水解的机械化学偶联和构象变化将DNA或蛋白质底物通过其中央通道穿入许多重要的生物过程。这些马达包含ATPase亚基的六聚环，其中高度保守的核苷酸结合结构域在亚基界面附近形成活性位点口袋，芳香孔环残基延伸到中央通道，用于底物结合和机械拉动。在过去的两年中，已解决了41个冷冻EM结构的底物结合AAA +转移酶，揭示了围绕底物多肽的孔环残基的螺旋楼梯排列方式，并表明了保守的移交机制。在螺旋排列中，亚基的垂直位置似乎与其核苷酸状态相关，从顶部的ATP结合到底部的ADP或载脂蛋白状态。描述特定马达多种构型的研究表明，ATP水解步骤与亚基移动之间的潜在耦合会推动底物。使用双环II型AAA +马达进行的实验揭示了单个亚基的两个ATPase域之间水解步骤的偏移，缺少芳香孔环的上部ATPase域经常形成平面环。这篇综述总结了近期研究为我们对六聚AAA +易位酶的结构和功能理解所提供的重要进展，