Ca2+ and calmodulin regulate the binding of filamin A to actin filaments

Filamin A (FLNa) cross-links actin filaments (F-actin) into three-dimensional gels in cells, attaches F-actin to membrane proteins, and is a scaffold that collects numerous and diverse proteins. We report that Ca2+-calmodulin binds the actin-binding domain (ABD) of FLNa and dissociates FLNa from F- actin, thereby dissolving (FLNaF)-F-.-actin gels. The FLNa ABD has two calponin homology domains (CH1 and CH2) separated by a linker. Recombinant CH1 but neither FLNa nor its ABD binds Ca2+-calmodulin in the absence of F- actin. Extending recombinant CH1 to include the negatively charged region linker domain makes it, like full-length FLNa, unable to bind Ca2+-calmodulin. Ca2+-calmodulin does, however, dissociate the FLNa ABD from F- actin provided that the CH2 domain is present. These findings identify the first evidence for direct regulation of FLNa, implicating amechanism whereby Ca2+-calmodulin selectively targets the (FLNaF)-F-.-actin complex.