Leiomodin creates a leaky cap at the pointed end of actin-thin filaments.
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 dat...
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| Format: | Article |
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Public Library of Science (PLoS)
2020-09-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3000848&type=printable |
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| author | Dmitri Tolkatchev Garry E Smith Lauren E Schultz Mert Colpan Gregory L Helms John R Cort Carol C Gregorio Alla S Kostyukova |
| author_facet | Dmitri Tolkatchev Garry E Smith Lauren E Schultz Mert Colpan Gregory L Helms John R Cort Carol C Gregorio Alla S Kostyukova |
| author_sort | Dmitri Tolkatchev |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1cbcaa851ce94502ace6c68ed797cc37 |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2020-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-1cbcaa851ce94502ace6c68ed797cc372025-02-05T05:30:21ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852020-09-01189e300084810.1371/journal.pbio.3000848Leiomodin creates a leaky cap at the pointed end of actin-thin filaments.Dmitri TolkatchevGarry E SmithLauren E SchultzMert ColpanGregory L HelmsJohn R CortCarol C GregorioAlla S KostyukovaImproper 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.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3000848&type=printable |
| spellingShingle | Dmitri Tolkatchev Garry E Smith Lauren E Schultz Mert Colpan Gregory L Helms John R Cort Carol C Gregorio Alla S Kostyukova Leiomodin creates a leaky cap at the pointed end of actin-thin filaments. PLoS Biology |
| title | Leiomodin creates a leaky cap at the pointed end of actin-thin filaments. |
| title_full | Leiomodin creates a leaky cap at the pointed end of actin-thin filaments. |
| title_fullStr | Leiomodin creates a leaky cap at the pointed end of actin-thin filaments. |
| title_full_unstemmed | Leiomodin creates a leaky cap at the pointed end of actin-thin filaments. |
| title_short | Leiomodin creates a leaky cap at the pointed end of actin-thin filaments. |
| title_sort | leiomodin creates a leaky cap at the pointed end of actin thin filaments |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3000848&type=printable |
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