title: Leiomodin-2 is an antagonist of tropomodulin-1 at the pointed end of the thin filaments in cardiac muscle.
abstract: Regulation of actin filament assembly is essential for efficient contractile activity in striated muscle. Leiomodin is an actin-binding protein and homolog of the pointed-end capping protein, tropomodulin. These proteins are structurally similar, sharing a common domain organization that includes two actin-binding sites. Leiomodin also contains a unique C-terminal extension that has a third actin-binding WH2 domain. Recently, the striated-muscle-specific isoform of leiomodin (Lmod2) was reported to be an actin nucleator in cardiomyocytes. Here, we have identified a function of Lmod2 in the regulation of thin filament lengths. We show that Lmod2 localizes to the pointed ends of thin filaments, where it competes for binding with tropomodulin-1 (Tmod1). Overexpression of Lmod2 results in loss of Tmod1 assembly and elongation of the thin filaments from their pointed ends. The Lmod2 WH2 domain is required for lengthening because its removal results in a molecule that caps the pointed ends similarly to Tmod1. Furthermore, Lmod2 transcripts are first detected in the heart after it has begun to beat, suggesting that the primary function of Lmod2 is to maintain thin filament lengths in the mature heart. Thus, Lmod2 antagonizes the function of Tmod1, and together, these molecules might fine-tune thin filament lengths.
authors.affiliation: Department of Cell Biology and Anatomy, and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Tsukada
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Pappas
authors.forename: Natalia
authors.initials: N
authors.lastname: Moroz
authors.forename: Parker B
authors.initials: PB
authors.lastname: Antin
authors.forename: Alla S
authors.initials: AS
authors.lastname: Kostyukova
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D032342:Muscle Cells / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014335:Tropomyosin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008840:Microfilament Proteins; D014335:Tropomyosin