Leiomodin creates a leaky cap at the pointed end of actin-thin filaments.

Autor: Tolkatchev D; Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, Washington, United States of America., Smith GE Jr; Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, Washington, United States of America., Schultz LE; Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, United States of America., Colpan M; Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, United States of America., Helms GL; The Center for NMR Spectroscopy, Washington State University, Pullman, Washington, United States of America., Cort JR; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, United States of America.; Institute of Biological Chemistry, Washington State University, Pullman, Washington, United States of America., Gregorio CC; Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, The University of Arizona, Tucson, Arizona, United States of America., Kostyukova AS; Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, Washington, United States of America.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2020 Sep 08; Vol. 18 (9), pp. e3000848. Date of Electronic Publication: 2020 Sep 08 (Print Publication: 2020).
DOI: 10.1371/journal.pbio.3000848
Abstrakt: Improper lengths of actin-thin filaments are associated with altered contractile activity and lethal myopathies. Leiomodin, a member of the tropomodulin family of proteins, is critical in thin filament assembly and maintenance; however, its role is under dispute. Using nuclear magnetic resonance data and molecular dynamics simulations, we generated the first atomic structural model of the binding interface between the tropomyosin-binding site of cardiac leiomodin and the N-terminus of striated muscle tropomyosin. Our structural data indicate that the leiomodin/tropomyosin complex only forms at the pointed end of thin filaments, where the tropomyosin N-terminus is not blocked by an adjacent tropomyosin protomer. This discovery provides evidence supporting the debated mechanism where leiomodin and tropomodulin regulate thin filament lengths by competing for thin filament binding. Data from experiments performed in cardiomyocytes provide additional support for the competition model; specifically, expression of a leiomodin mutant that is unable to interact with tropomyosin fails to displace tropomodulin at thin filament pointed ends and fails to elongate thin filaments. Together with previous structural and biochemical data, we now propose a molecular mechanism of actin polymerization at the pointed end in the presence of bound leiomodin. In the proposed model, the N-terminal actin-binding site of leiomodin can act as a "swinging gate" allowing limited actin polymerization, thus making leiomodin a leaky pointed-end cap. Results presented in this work answer long-standing questions about the role of leiomodin in thin filament length regulation and maintenance.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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