Structural basis of fast- and slow-severing actin-cofilactin boundaries.
Structural basis of fast- and slow-severing actin-cofilactin boundaries.
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DOI：
10.1016/j.jbc.2021.100337
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
De La Cruz EM
中科院分区：
文献类型：
--
作者：
Hocky GM;Sindelar CV;Cao W;Voth GA;De La Cruz EM
调节蛋白的ADF/cofilin家族的成员协同结合肌动蛋白丝，局部改变肌动蛋白亚基构象和方向，并在裸露和cofilin占据的片段之间的“边界”切断肌动蛋白丝。由于肌动蛋白丝的固有极性，结合的cofilin的簇引入两种不同类别的边界，一种在簇的“尖”端侧，另一种在簇的“倒钩”端侧;在簇的尖端侧（“快速切断”边界）比倒钩端侧（“缓慢切断”边界）更容易发生切断。最近的电子低温显微镜（cryo-EM）模型的缓慢切断边界显示的结构“缺陷”的接口，可能有助于切断。然而，快速切断边界的结构仍然不确定。在这里，我们使用广泛的分子动力学模拟产生两个切断边界的原子分辨率模型。我们的平衡模拟模型的慢切断边界是一致的cryo-EM结构模型。模拟表明，肌动蛋白亚基在两个边界采取的结构之间的裸和cofilin绑定肌动蛋白亚基的中间。这些“中间”状态已经损害了亚基间的接触，但那些在缓慢切断的边界是稳定的cofilin桥接相互作用，占其较低的碎片化概率。从cofilactin丝中去除cofilin蛋白的模拟有利于一种机制，其中需要两个连续结合的cofilins的簇来完全稳定cofilactin构象，促进合作结合相互作用，并加速丝切断。总之，这些研究提供了一个分子尺度的基础，发展粗粒度和理论描述的cofilin介导的肌动蛋白丝切断。
Members of the ADF/cofilin family of regulatory proteins bind actin filaments cooperatively, locally change actin subunit conformation and orientation, and sever filaments at “boundaries” between bare and cofilin-occupied segments. A cluster of bound cofilin introduces two distinct classes of boundaries due to the intrinsic polarity of actin filaments, one at the “pointed” end side and the other at the “barbed” end-side of the cluster; severing occurs more readily at the pointed end side of the cluster (“fast-severing” boundary) than the barbed end side (“slow-severing” boundary). A recent electron-cryomicroscopy (cryo-EM) model of the slow-severing boundary revealed structural “defects” at the interface that potentially contribute to severing. However, the structure of the fast-severing boundary remains uncertain. Here, we use extensive molecular dynamics simulations to produce atomic resolution models of both severing boundaries. Our equilibrated simulation model of the slow-severing boundary is consistent with the cryo-EM structural model. Simulations indicate that actin subunits at both boundaries adopt structures intermediate between those of bare and cofilin-bound actin subunits. These “intermediate” states have compromised intersubunit contacts, but those at the slow-severing boundary are stabilized by cofilin bridging interactions, accounting for its lower fragmentation probability. Simulations where cofilin proteins are removed from cofilactin filaments favor a mechanism in which a cluster of two contiguously bound cofilins is needed to fully stabilize the cofilactin conformation, promote cooperative binding interactions, and accelerate filament severing. Together, these studies provide a molecular-scale foundation for developing coarse-grained and theoretical descriptions of cofilin-mediated actin filament severing.
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影响因子：
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作者：
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作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1103/physreve.101.032409
发表时间：
2020-03
期刊：
Physical review. E
影响因子：
--
作者：
Jermyn AS;Cao W;Elam WA;De La Cruz EM;Lin MM
通讯作者：
Lin MM