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Mechanisms of actin filament severing and elongation by formins

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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.

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Correspondence to Roberto Dominguez.

Supplementary information

Supplementary Information

Supplementary Figures 1–14.

Reporting Summary

Supplementary Video 1

Structures of INF2 and Dia1 in the middle of F-actin. Comparison of the structures of INF2 and Dia1 bound in the middle of F-actin, highlighting differences in position between the up and down state of INF2 with Dia1 in the middle.

Supplementary Video 2

Proposed hand-over-hand F-actin severing mechanism by INF2. Proposed hand-over-hand mechanism of F-actin severing by INF2. The video shows cryo-EM maps and models of proposed steps of the severing mechanism (see also Fig. 2 in main text).

Supplementary Video 3

Structures of INF2 and Dia1 at the barbed end. Comparison of the structures of INF2 and Dia1 at the barbed end, highlighting differences in position between their FH2s.

Supplementary Video 4

Proposed LERA elongation mechanism. Proposed LERA (Load, Exchange, Release, Advance) elongation mechanism of F-actin by formins. The video shows cryo-EM maps and models of proposed steps of the elongation mechanism (see also Fig. 3 in main text).

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Palmer, N.J., Barrie, K.R. & Dominguez, R. Mechanisms of actin filament severing and elongation by formins. Nature (2024).

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