Filamin structure, function and mechanics: are altered filamin-mediated force responses associated with human disease?

Abstract

The cytoskeleton framework is essential not only for cell structure and stability but also for dynamic processes such as cell migration, division and differentiation. The F-actin cytoskeleton is mechanically stabilised and regulated by various actin-binding proteins, one family of which are the filamins that cross-link F-actin into networks that greatly alter the elastic properties of the cytoskeleton. Filamins also interact with cell membraneassociated extracellular matrix receptors and intracellular signalling proteins providing a potential mechanism for cells to sense their external environment by linking these signalling systems. The stiffness of the external matrix to which cells are attached is an important environmental variable for cellular behaviour. In order for a cell to probe matrix stiffness, a mechanosensing mechanism functioning via alteration of protein structure and/or binding events in response to external tension is required. Current structural, mechanical, biochemical and human disease-associated evidence suggests filamins are good candidates for a role in mechanosensing.

A proteomic approach to understanding the pathogenesis of idiopathic macular hole formation

“…Vinculin plays a role in binding and rearranging the actin cytoskeleton [ 29 ]. Filamin-A plays a role in cross-linking and stabilizing the F-actin cytoskeleton [ 30 ].…”

Postnatal Role of the Cytoskeleton in Adult Epileptogenesis

“…2007 ; Wynshaw-Boris 2007 ; Rakhade and Jensen 2009 ; Gardiner and Marc 2010 ; Pramparo et al. 2011 ; Sutherland-Smith 2011 ; Stouffer et al. 2016 ; Wei et al.…”

Phosphorylation of HspB1 regulates its mechanosensitive molecular chaperone interaction with native filamin C

“…Next we expressed EEF-tagged human FLNC domains 18-21, encompassing the apparent HspB1 binding site (39), and full-length human HspB1 including a T7 tag. Pulling down the HspB1 protein with the T7 antibody co-immunoprecipitated FLNC d18-21 (Fig.…”

“…The motivation for this stemmed from the observation that the filamin distal region (Fig. 1A) undergoes extension in vivo (43), with FLNA domains even predicted to be able to unfold fully prior to breakage of the dimer interface, at physiologically relevant forces and loading rates (1, 39). As a proxy for mechanical stress, we performed gas-phase experiments in which protein ions are activated by collisions with inert gas, leading to conformational perturbations and Coulombic-repulsion-driven chain extension (64–66).…”

“…FLNC contains a large insertion within d20, and less is known about its structure and the molecular basis of its roles. Evidence that FLNC can sense local force includes: functionality that necessitates a degree of plasticity in response to tension (39); 73% sequence identity and overlapping roles and binding partners with FLNA (40, 41); the ability to protect myofibrillar structural integrity (42); and differential in-cell labelling of shielded cysteines with applied force (43).…”