title: Mechanisms of leiomodin 2-mediated regulation of actin filament in muscle cells.
abstract: Leiomodin (Lmod) is a class of potent tandem-G-actin-binding nucleators in muscle cells. Lmod mutations, deletion, or instability are linked to lethal nemaline myopathy. However, the lack of high-resolution structures of Lmod nucleators in action severely hampered our understanding of their essential cellular functions. Here we report the crystal structure of the actin-Lmod2162-495 nucleus. The structure contains two actin subunits connected by one Lmod2162-495 molecule in a non-filament-like conformation. Complementary functional studies suggest that the binding of Lmod2 stimulates ATP hydrolysis and accelerates actin nucleation and polymerization. The high level of conservation among Lmod proteins in sequence and functions suggests that the mechanistic insights of human Lmod2 uncovered here may aid in a molecular understanding of other Lmod proteins. Furthermore, our structural and mechanistic studies unraveled a previously unrecognized level of regulation in mammalian signal transduction mediated by certain tandem-G-actin-binding nucleators.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Chen
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Fengyun
authors.initials: F
authors.lastname: Ni
authors.affiliation: Life Sciences Collaborative Access Team, Synchrotron Research Center, Northwestern University, Argonne, IL 60439;
authors.forename: Elena
authors.initials: E
authors.lastname: Kondrashkina
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Bioengineering, Rice University, Houston, TX 77005 jpma@bcm.edu qinghuaw@bcm.edu.
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Ma
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030; jpma@bcm.edu qinghuaw@bcm.edu.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D018360:Crystallography, X-Ray; D004331:Drosophila melanogaster; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics; D032342:Muscle Cells; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics; D020836:Protein Structure, Quaternary; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: C528309:LMOD2 protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins
keywords: actin nucleation; nemaline myopathy; pointed-end elongation