Asymmetric processing of a substrate protein in sequential allosteric cycles of AAA+ nanomachines.
Asymmetric processing of a substrate protein in sequential allosteric cycles of AAA+ nanomachines.
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AAA 纳米机器连续变构循环中底物蛋白的不对称加工。
DOI：
10.1063/1.4817410
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
G. Stan
中科院分区：
文献类型：
--
作者：
Andrea N. Kravats;Sam Tonddast;Ryan J Bucher;G. Stan
必需的蛋白质质量控制包括由强大的环形AAA+（与各种细胞活动相关的ATP酶）纳米机器执行的底物蛋白（SP）解折叠和易位机制。这些SP重塑作用受到突出到中央通道中的AAA+环施加的机械力的影响。已提出作为重复SP环相互作用基础的连续环内变构运动包括单个AAA+亚基的顺时针（CW）、逆时针（CCW）或随机（R）构象转变。为了探索这些变构机制对解折叠酶和转位酶功能的影响，我们对单环ClpY ATP酶或双环p97 ATP酶处理的全α SP的粗粒模型进行Langevin动力学模拟。我们发现，在所有三种变构机制中，SP都沿着一组共同的途径经历构象转变，这表明ClpY机器提供的主动工作涉及单环-SP相互作用。然而，SP展开和易位的速率和产量是由机制依赖的环-SP结合事件控制的，如CW变构中SP处理的时间尺度比CCW和R变构更快所示。变构机制的独特功效是由于相邻亚基的不对称协作，其涉及AAA+环的CW偏置结构运动并导致施加到SP上的CW相容扭矩。突变ClpY环的额外模拟，其使亚基的子集催化缺陷或降低其SP结合亲和力，揭示基于亚基的构象转变在SP重塑中起主要作用。基于这些结果，我们预测，最低功能的AAA+环包括三个活性亚基，其中只有两个是相邻的。
Essential protein quality control includes mechanisms of substrate protein (SP) unfolding and translocation performed by powerful ring-shaped AAA+ (ATPases associated with various cellular activities) nanomachines. These SP remodeling actions are effected by mechanical forces imparted by AAA+ loops that protrude into the central channel. Sequential intra-ring allosteric motions, which underlie repetitive SP-loop interactions, have been proposed to comprise clockwise (CW), counterclockwise (CCW), or random (R) conformational transitions of individual AAA+ subunits. To probe the effect of these allosteric mechanisms on unfoldase and translocase functions, we perform Langevin dynamics simulations of a coarse-grained model of an all-alpha SP processed by the single-ring ClpY ATPase or by the double-ring p97 ATPase. We find that, in all three allosteric mechanisms, the SP undergoes conformational transitions along a common set of pathways, which reveals that the active work provided by the ClpY machine involves single loop-SP interactions. Nevertheless, the rates and yields of SP unfolding and translocation are controlled by mechanism-dependent loop-SP binding events, as illustrated by faster timescales of SP processing in CW allostery compared with CCW and R allostery. The distinct efficacy of allosteric mechanisms is due to the asymmetric collaboration of adjacent subunits, which involves CW-biased structural motions of AAA+ loops and results in CW-compatible torque applied onto the SP. Additional simulations of mutant ClpY rings, which render a subset of subunits catalytically-defective or reduce their SP binding affinity, reveal that subunit-based conformational transitions play the major role in SP remodeling. Based on these results we predict that the minimally functional AAA+ ring includes three active subunits, only two of which are adjacent.
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影响因子：
16
作者：
Christoph Spiess;Erik J. Miller;A. J. McClellan;J. Frydman
通讯作者：
Christoph Spiess;Erik J. Miller;A. J. McClellan;J. Frydman
影响因子：
5.7
作者：
Davies, Jason M.;Brunger, Axel T.;Weis, William I.
通讯作者：
Weis, William I.
DOI：
10.1016/s0006-291x(02)02840-1
发表时间：
2003-01-10
影响因子：
3.1
作者：
Wang, Q;Song, CC;Li, CCH
通讯作者：
Li, CCH
正态模式分析揭示了古菌伴侣蛋白热体的环内变构通讯较弱。
影响因子：
3.4
作者：
Jayasinghe,Manori;Shrestha,Pooja;Wu,Xiongwu;Tehver,Riina;Stan,George
通讯作者：
Stan,George