Nature:肌動蛋白絲被形成素切斷和伸長的機制

2024年6月6日,來自美國賓夕法尼亞大學佩雷爾曼醫學院Roberto Dominguez團隊在《自然》雜志上發表了標題為“Mechanisms of actin filament severing and elongation by formins.”的研究成果,提出了肌動蛋白絲形成素切斷和伸長的機制。

 

肌動蛋白絲被形成素切斷和伸長的機制

 

據介紹,人類表達15種形成素,它們在細胞分裂、細胞運動和機械傳導等以肌動蛋白為基礎的過程中發揮著關鍵作用。然而,缺乏與肌動蛋白絲(F-actin)結合的結構一直是理解形成素功能的主要障礙。雖然形成素以其成核和伸長F-actin的能力而聞名,但一些形成素可以額外解聚、切斷或捆綁F-actin。兩種哺乳動物形成素(INF2Dia1),就是這種多樣性的例證。INF2表現出強大的切斷活性但伸長較弱,而Dia1具有強大的伸長活性但不切斷。

 

使用冷凍電鏡(cryo-EM),研究人員揭示了INF2和Dia1與F-actin的中間端和倒鉤端結合的五種結構狀態。INF2和Dia1與這些位點的結合不同,這與其不同的活性一致。INF2的FH2和WH2結構域被定位為切斷F-actin,而Dia1似乎不適合切斷。結構還顯示了輪profilin-actin是如何傳遞到快速生長的倒鉤末端的,以及隨后進入的單體如何轉變為F-actin構象和釋放抑制蛋白。

 

總之,這里提出的七種結構提供了通過形成素切斷和延伸F-actin的機制的逐步可視化。

 

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.

 

文章來源:

Palmer, Nicholas J., Barrie, Kyle R. et al,Mechanisms of actin filament severing and elongation by formins.DOI: 10.1038/s41586-024-07637-0, Nature:最新IF:69.504

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