Structural basis of filamin A functions

Filamin A ( FLNa) can effect orthogonal branching of F- actin and bind many cellular constituents. FLNa dimeric subunits have N- terminal spectrin family F- actin binding domains ( ABDs) and an elongated. flexible segment of 24 immunoglobulin ( Ig) repeats. We generated a library of FLNa fragments to examine their F- actin binding to de. ne the structural properties of FLNa that enable its various functions. We. find that Ig repeats 9 - 15 contain an F- actin - binding domain necessary for high avidity F- actin binding. Ig repeats 16 - 24, where most FLNa- binding partners interact, do not bind F- actin, and thus F- actin does not compete with Ig repeat 23 ligand, FilGAP. Ig repeats 16 - 24 have a compact structure that suggests their unfolding may accommodate pre- stress mediated stiffening of F- actin networks, partner binding, mechanosensing, and mechanoprotection properties of FLNa. Our results also establish the orientation of FLNa dimers in F- actin branching. Dimerization, mediated by FLNa Ig repeat 24, accounts for rigid high- angle FLNa/ F- actin branching resistant to bending by thermal forces, and high avidity F- actin binding and cross- linking.