Actin Filament Nucleation by Smooth Muscle Leiomodin-1

Abstract

The formation of new filaments is an essential, but kinetically unfavorable, step in actin cytoskeleton remodeling. In cells nucleation has to be catalyzed by proteins called nucleators that bring together at least two actin monomers and stabilize a polymerization nucleus. Among known filament nucleators Leiomodin (Lmod) is the only one specifically expressed in muscle cells. Lmod is related to the F-actin pointed-end capping protein tropomodulin (Tmod), with which it shares two actin-binding sites: a flexible N-terminal region and a leucine-rich repeat (LRR) domain. In addition, Lmod contains a unique C-terminal extension that features a WH2 domain, another actin-binding site.There are three muscle-type specific isoforms of Lmod: smooth muscle Lmod1, cardiac and striated muscle Lmod2, and the fetal isoform Lmod3. To date, only Lmod2 has been shown to nucleate actin filaments. Lmod1 is quite different in sequence from Lmod2 (37% identity, most of which is concentrated in the LRR). Here we demonstrate that despite these differences smooth muscle Lmod1 is also an actin filament nucleator. However its activity and mechanism of nucleation vary significantly from that of Lmod2.