Force-modulated structural landscape of the catch bonding F-actin crosslinker α-actinin-4

Authors

Chin, A. C., Mukadum, F., Reynolds, M. J., Hocky, G. M., Alushin, G. M.

Abstract

Catch bonds, noncovalent supramolecular interactions whose lifetimes are increased by force, are ubiquitous in mechanical signaling pathways. The structural mechanisms of catch-bonding proteins remain unclear, hampering efforts to decipher how they are dysregulated in disease and exploit them therapeutically. The crosslinker -actinin-4 (ACTN4) forms catch bonds with actin filaments (F-actin) to support the function of kidney podocytes, and its force-insensitive K255E variant causes autosomal dominant focal segmental glomerulosclerosis (FSGS). Using cryo-electron microscopy (cryo-EM), we find that wild-type ACTN4 engages F-actin in two modes, which biochemical experiments and molecular dynamics simulations assign as strong- and weak-binding states, while K255E ACTN4 only populates the strong binding state. By implementing a cryo-EM platform for applying tension across crosslinker-F-actin interfaces using myosin motors, we find that force promotes a weak-to-strong binding transition for wild-type ACTN4, consistent with a two-state catch bond model. Beyond providing mechanistic insight into how the K255E mutation disrupts ACTN4 F-actin catch-bonding in FSGS, this approach enables structural dissection of force-sensitive actin-binding proteins.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Mar 2026.

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