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
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来源:科学网 小柯机器人