Molecular origins of cofilin-linked changes in actin filament mechanics.
Molecular origins of cofilin-linked changes in actin filament mechanics.
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DOI：
10.1016/j.jmb.2013.01.020
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发表时间：
2013-04-12
影响因子：
5.6
通讯作者：
Voth, Gregory A.
中科院分区：
文献类型：
--
作者：
Fan, Jun;Saunders, Marissa G.;Haddadian, Esmael J.;Freed, Karl F.;De La Cruz, Enrique M.;Voth, Gregory A.
肌动蛋白调节蛋白cofilin在肌动蛋白组装动力学中起着核心作用，通过切断细丝和增加亚基添加和解离的末端浓度。Cofilin绑定修改肌动蛋白丝的平均结构和机械性能，从而促进部分修饰的丝在裸露和cofilin修饰的片段的边界处的片段化。尽管有大量证据表明丝蛋白依赖性的丝结构和力学变化，但尚不清楚这两个过程在分子水平上是如何联系起来的。在这里，我们使用分子动力学模拟和粗粒度的分析，以评估由于cofilin绑定的丝顺应性的变化的分子起源。具有结合的丝切蛋白的丝亚基不太平坦，并且比裸丝亚基保持显著更开放的核苷酸裂缝。修饰后的丝段比裸丝段扭曲更少、更细（仅考虑肌动蛋白）、连接更少，这降低了丝的弯曲持久长度和扭转刚度。使用粗粒化作为分析方法揭示了cofilin结合增加了相邻长轴丝亚基之间的平均距离，从而削弱了它们之间的相互作用。相反，一部分侧丝亚基接触更紧密，可能更强的cofilin结合。一个cofilactin界面接触低温电子显微镜确定在310 K进行的模拟过程中是不稳定的，这表明这种特殊的相互作用可能是短暂的，在环境温度下。这些结果揭示了可能促进丝切断的肌动蛋白丝力学的cofilin依赖性变化的分子起源。
The actin regulatory protein cofilin plays a central role in actin assembly dynamics by severing filaments and increasing the concentration of ends from which subunits add and dissociate. Cofilin binding modifies the average structure and mechanical properties of actin filaments, thereby promoting fragmentation of partially decorated filaments at boundaries of bare and cofilin-decorated segments. Despite extensive evidence for cofilin-dependent changes in filament structure and mechanics, it is unclear how the two processes are linked at the molecular level. Here, we use molecular dynamics simulations and coarse-grained analyses to evaluate the molecular origins of the changes in filament compliance due to cofilin binding. Filament subunits with bound cofilin are less flat and maintain a significantly more open nucleotide cleft than bare filament subunits. Decorated filament segments are less twisted, thinner (considering only actin), and less connected than their bare counterparts, which lowers the filament bending persistence length and torsional stiffness. Using coarse-graining as an analysis method reveals that cofilin binding increases the average distance between the adjacent long-axis filament subunit, thereby weakening their interaction. In contrast, a fraction of lateral filament subunit contacts are closer and presumably stronger with cofilin binding. A cofilactin interface contact identified by cryo-electron microscopy is unstable during simulations carried out at 310K, suggesting that this particular interaction may be short-lived at ambient temperatures. These results reveal the molecular origins of cofilin-dependent changes in actin filament mechanics that may promote filament severing.
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影响因子：
64.8
作者：
EGELMAN, EH;FRANCIS, N;DEROSIER, DJ
通讯作者：
DEROSIER, DJ
影响因子：
7.8
作者：
Galkin, Vitold E;Orlova, Albina;VanLoock, Margaret S;Shvetsov, Alexander;Reisler, Emil;Egelman, Edward H
通讯作者：
Egelman, Edward H
影响因子：
5.6
作者：
Bobkov, AA;Muhlrad, A;Reisler, E
通讯作者：
Reisler, E
影响因子：
16
作者：
Andrianantoandro, Ernesto;Pollard, Thomas D.
通讯作者：
Pollard, Thomas D.
影响因子：
2.4
作者：
Deriu, Marco A.;Bidone, Tamara C.;Morbiducci, Umberto
通讯作者：
Morbiducci, Umberto