Cracked actin filaments as mechanosensitive receptors.

Actin filament networks are exposed to mechanical stimuli, but the effect of strain on actin filament structure has not been well-established in molecular detail. This is a critical gap in understanding because the activity of a variety of actin-binding proteins have recently been determined to be altered by actin filament strain. We therefore used all-atom molecular dynamics simulations to apply tensile strains to actin filaments and find that changes in actin subunit organization are minimal in mechanically strained, but intact, actin filaments. However, a conformational change disrupts the critical D-loop to W-loop connection between longitudinal neighboring subunits, which leads to a metastable cracked conformation of the actin filament, whereby one protofilament is broken prior to filament severing. We propose that the metastable crack presents a force-activated binding site for actin regulatory factors that specifically associate with strained actin filaments. Through protein-protein docking simulations, we find that 43 evolutionarily-diverse members of the dual zinc finger containing LIM domain family, which localize to mechanically strained actin filaments, recognize two binding sites exposed at the cracked interface. Furthermore, through its interactions with the crack, LIM domains increase the length of time damaged filaments remain stable. Our findings propose a new molecular model for mechanosensitive binding to actin filaments. Cells continually experience mechanical strain, which has been observed to alter the interactions between actin filaments and mechanosensitive actin-binding proteins in recent experimental studies. However, the structural basis of this mechanosensitivity is not well understood. We used molecular dynamics and protein-protein docking simulations to investigate how tension alters the actin filament binding surface and interactions with associated proteins. We identified a novel metastable cracked conformation of the actin filament, whereby one protofilament breaks before the other, presenting a unique strain-induced binding surface. Mechanosensitive LIM domain actin-binding proteins can then preferentially bind the cracked interface, and this association stabilizes damaged actin filaments.

Citation

Vilmos Zsolnay, Margaret L Gardel, David R Kovar, Gregory A Voth. Cracked actin filaments as mechanosensitive receptors. bioRxiv : the preprint server for biology. 2023 Jun 28

PMID: 37425801

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