美国宾夕法尼亚大学佩雷尔曼医学院Roberto Dominguez团队近期取得重要工作进展，他们最新研究提出了肌动蛋白丝被成形素切断和伸长的机制。相关研究成果2024年6月6日在线发表于《自然》杂志上。

据介绍，人类表达15种形成素，它们在细胞分裂、细胞运动和机械传导等以肌动蛋白为基础的过程中发挥着关键作用。然而，缺乏与肌动蛋白丝（F-actin）结合的结构一直是理解形成素功能的主要障碍。虽然形成素以其成核和伸长F-actin的能力而闻名，但一些形成素可以额外解聚、切断或捆绑F-actin。两种哺乳动物形成素（INF2和Dia1），就是这种多样性的例证。INF2表现出强大的切断活性但伸长较弱，而Dia1具有强大的伸长活性但不切断。

使用冷冻电镜（cryo-EM），研究人员揭示了INF2和Dia1与F-actin的中间端和倒钩端结合的五种结构状态。INF2和Dia1与这些位点的结合不同，这与其不同的活性一致。INF2的FH2和WH2结构域被定位为切断F-actin，而Dia1似乎不适合切断。结构还显示了轮profilin-actin是如何传递到快速生长的倒钩末端的，以及随后进入的单体如何转变为F-actin构象和释放抑制蛋白。

总之，这里提出的七种结构提供了通过形成素切断和延伸F-actin的机制的逐步可视化。

附：英文原文

Title: Mechanisms of actin filament severing and elongation by formins

Author: Palmer, Nicholas J., Barrie, Kyle R., Dominguez, Roberto

Issue&Volume: 2024-06-06

Abstract: Humans express fifteen formins, playing crucial roles in actin-based processes, such as cytokinesis, cell motility, and mechanotransduction 1,2. However, the lack of structures bound to the actin filament (F-actin) has been a major impediment to understanding formin function. While formins are known for their ability to nucleate and elongate F-actin 3-7, some formins can additionally depolymerize, sever, or bundle F-actin. Two mammalian formins, inverted formin-2 (INF2) and diaphanous-1 (Dia1), exemplify this diversity. INF2 displays potent severing activity but elongates weakly 8-11, whereas Dia1 has potent elongation activity but does not sever 4,8. Using cryo-electron microscopy (cryo-EM), we reveal five structural states of INF2 and two of Dia1 bound to the middle and barbed end of F-actin. INF2 and Dia1 bind differently to these sites, consistent with their distinct activities. The FH2 and WH2 domains of INF2 are positioned to sever F-actin, whereas Dia1 appears unsuited for severing. Structures also show how profilin-actin is delivered to the fast-growing barbed end, and how this is followed by a transition of the incoming monomer into the F-actin conformation and the release of profilin. Combined, the seven structures presented here provide step-by-step visualization of the mechanisms of F-actin severing and elongation by formins.

DOI: 10.1038/s41586-024-07637-0

Source: https://www.nature.com/articles/s41586-024-07637-0