Cellular force-sensing through actin filaments

Abstract

The actin cytoskeleton orchestrates cell mechanics and facilitates the physical integration of cells into tissues, while tissue-scale forces and extracellular rigidity in turn govern cell behaviour. Here, we discuss recent evidence that actin filaments (F-actin), the core building blocks of the actin cytoskeleton, also serve as molecular force sensors. We delineate two classes of proteins, which interpret forces applied to F-actin through enhanced binding interactions: 'mechanically tuned' canonical actin-binding proteins, whose constitutive F-actin affinity is increased by force, and 'mechanically switched' proteins, which bind F-actin only in the presence of force. We speculate mechanically tuned and mechanically switched actin-binding proteins are biophysically suitable for coordinating cytoskeletal force-feedback and mechanical signalling processes, respectively. Finally, we discuss potential mechanisms mediating force-activated actin binding, which likely occurs both through the structural remodelling of F-actin itself and geometric rearrangements of higher-order actin networks. Understanding the interplay of these mechanisms will enable the dissection of force-activated actin binding's specific biological functions.

Keywords: actin; actin-binding proteins; cytoskeleton; mechanobiology; mechanosensation; mechanotransduction.

Figure 1.. Two biophysical mechanisms for force-activated actin binding.

(A) Molecular tuning, where force enhances the F-actin affinity of a canonical ABP (e.g. α-catenin, which we speculate enhances cell-cell adhesion). (B) Molecular switching, where force licenses F-actin binding of a protein that does not bind in the absence of force (e.g. the LIM protein FHL2, which is retained in the cytoplasm through tensed F-actin binding). Blue lines, actin filaments. Orange rectangles, ABPs. Green ellipses / circles, adherens junctions (A) and focal adhesions (B). Panel B is adapted from [7].

Figure 2.. Potential structural mechanisms for force-activated actin binding.

(A) Left: Surface representation of canonical F-actin. Right: Ribbon representation of an actin subunit superimposed with balls representing the centroid of each subdomain connected by sticks (adapted from [103]). ADP is displayed in space-filling representation in gold. Figures were generated from a cryo-EM structure of ADP F-actin (PDB: 7R8V) [123] using UCSF ChimeraX [124]. (B-C) Plausible types of mechanically-regulated conformational transitions in individual actin filaments: (B) architectural remodeling, where the lattice arrangement of actin protomers is modified; (C) subunit deformation, where the conformation of individual protomers is altered (e.g. through subdomain rearrangements). While architectural remodeling and subunit deformation can theoretically occur independently, they are likely to be coupled. (D) Mechanical regulation through network geometry remodeling, where a multi-filament binding ABP is sensitive to inter-filament spacing and filament number density rather than the conformation of individual filaments.