Leiomodin creates a leaky cap at the pointed end of actin-thin filaments
Open Access
- 8 September 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 18 (9), e3000848
- https://doi.org/10.1371/journal.pbio.3000848
Abstract
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.Funding Information
- National Institutes of Health (GM120137)
- National Institutes of Health (HL123078)
- National Institute of General Medical Sciences (T32 GM008336)
- American Heart Association (19POST34450023)
- National Heart, Lung, and Blood Institute (T32HL007249)
- National Institutes of Health (1F31AR076209)
- National Institutes of Health (GM120137)
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