Stress Accumulation Originating from Mechanical Asymmetry Promotes Actin Filament Severing at Boundaries of Bare and Cofilin-Decorated Segments

The regulatory protein, cofilin, severs actin filaments and increases the number of ends from which subunits add and dissociate. Structural and biochemical analyses demonstrate that cofilin binding alters the conformation and mechanics of actin filaments such that cofilin-decorated filaments are ∼20-fold more compliant in bend and twist than native actin filaments. Equilibrium and kinetic binding models as well as direct visualization of cofilin binding to filaments favor a mechanism in which severing occurs at or near boundaries of bare and cofilin-decorated segments. It is hypothesized that shear stress associated with conformational fluctuations accumulates locally at boundaries of mechanical asymmetry, thereby leading to preferential severing at junctions of bare and cofilin-decorated segments. In this work, we evaluate if mechanical and conformational periodicity in filaments promotes stress accumulation at junctions of asymmetry (i.e. boundaries). We have derived mathematical expressions of the actin filament elastic free energy, accounting for contributions from bending, twisting and twist-bend coupling, and used a computational modeling approach to evaluate the distribution of energy and stress of model filaments strained by external mechanical (buckling or torque) loads applied to filament ends. Our results indicate that mechanical asymmetry introduced by cofilin binding promotes the accumulation of shear stress at boundaries between bare and cofilin-decorated segments that likely increases the probability of failure (i.e. severing) under active or passive, thermal deformation, analogous to the fracture of some non-protein materials. Elastic coupling between twisting and bending is critical for stress accumulation at boundaries.