title: How Leiomodin and Tropomodulin use a common fold for different actin assembly functions.
abstract: How proteins sharing a common fold have evolved different functions is a fundamental question in biology. Tropomodulins (Tmods) are prototypical actin filament pointed-end-capping proteins, whereas their homologues, Leiomodins (Lmods), are powerful filament nucleators. We show that Tmods and Lmods do not compete biochemically, and display similar but distinct localization in sarcomeres. Changes along the polypeptide chains of Tmods and Lmods exquisitely adapt their functions for capping versus nucleation. Tmods have alternating tropomyosin (TM)- and actin-binding sites (TMBS1, ABS1, TMBS2 and ABS2). Lmods additionally contain a C-terminal extension featuring an actin-binding WH2 domain. Unexpectedly, the different activities of Tmods and Lmods do not arise from the Lmod-specific extension. Instead, nucleation by Lmods depends on two major adaptations-the loss of pointed-end-capping elements present in Tmods and the specialization of the highly conserved ABS2 for recruitment of two or more actin subunits. The WH2 domain plays only an auxiliary role in nucleation.
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Boczkowska
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Rebowski
authors.affiliation: Institute of Biotechnology, PO Box 56, 00014 University of Helsinki, Helsinki, Finland.
authors.forename: Elena
authors.initials: E
authors.lastname: Kremneva
authors.affiliation: Institute of Biotechnology, PO Box 56, 00014 University of Helsinki, Helsinki, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Lappalainen
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Dominguez
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D051348:Tropomodulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; C528309:LMOD2 protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins; C495829:TMOD1 protein, human; D051348:Tropomodulin