How cofilin severs an actin filament

Abstract

The actin regulatory protein, cofilin, promotes actin assembly dynamics by severing filaments and increasing the number of ends from which subunits add and dissociate. Recent studies provide biophysical descriptions of cooperative filament interactions in energetic, mechanical and structural terms. A one-dimensional Ising model with nearest-neighbor interactions permits thermodynamic analysis of cooperative binding and indicates that one or a few cofilin molecules can sever a filament. Binding and cooperative interactions are entropically driven. A significant fraction of the binding free energy results from the linked dissociation of filament-associated ions (polyelectrolyte effect), which modulate filament structure, stability and mechanics. The remaining binding free energy and essentially all of the cooperative free energy arise from the enhanced conformational dynamics of the cofilactin complex. Filament mechanics are modulated by cofilin such that cofilin-saturated filaments are approximately 10- to 20-fold more compliant in bending and twisting than bare filaments. Cofilin activity is well described by models in which discontinuities in topology, mechanics and conformational dynamics generate stress concentration and promote fracture at junctions of bare and decorated segments, analogous to the grain boundary fracture of crystalline materials and the thermally driven formation of shear transformation zones in colloidal glass.

Abl2/Abl-related Gene Stabilizes Actin Filaments, Stimulates Actin Branching by Actin-related Protein 2/3 Complex, and Promotes Actin Filament Severing by Cofilin

“…Cofilin severs actin filaments optimally when a low density of cofilin is bound along the filament, whereas filaments saturated with cofilin are stable (28). The (I/L)WEQ domain is required for Arg to promote severing by cofilin (Fig.…”

Actin Mechanics and Fragmentation

“…in the absence of applied external loads) is weak and presumably dominated by thermodynamic effects originating from structural phase discontinuities at boundaries between bare and decorated segments. Boundaries fragment at smaller deformations than either parent filament (50), suggesting that boundaries are "bad joints" that are susceptible to fragmentation, analogous to the interfacial fracture of some non-protein materials (12). Srv2/CAP (cyclase-associated protein) may enhance severing by cofilin by inducing further conformational changes at boundaries (57).…”

“…For example, active forces generated by contractile proteins may play a more dominant role (8,11,12). The mechanical properties and response of filaments are central to understanding fragmentation in this context because the mechanical heterogeneity and discontinuities introduced by cofilin will lead to unique behaviors that deviate from mechanically homogenous, bare actin filaments (40).…”

The actin filament twist changes abruptly at boundaries between bare and cofilin-decorated segments

“…Members of the cofilin/ADF family of actin regulatory proteins (1,2) bind actin filaments cooperatively (3)(4)(5) and promote severing preferentially at and near junctions between bare and cofilin-decorated (cofilactin) segments (3,(5)(6)(7)(8), hereafter referred to as boundaries. Cofilin alters the average actin filament twist (9) and subunit tilt (10,11).…”

“…Estimates of the length over which cofilininduced conformational changes and cooperative binding interactions propagate along actin vary, ranging from N = 1-2 up to N > 100 subunits (3,5,(12)(13)(14)(15)(16)(17)(18)(19)(20). Equilibrium (3,6,12,21) and transient kinetic (12,14) binding data are well described by models invoking positive cooperativity between nearest neighbors (N = 1-2).…”