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dc.contributor.authorLy, Thu
dc.contributor.authorMoroz, Natalia
dc.contributor.authorPappas, Christopher T
dc.contributor.authorNovak, Stefanie M
dc.contributor.authorTolkatchev, Dmitri
dc.contributor.authorWooldridge, Dayton
dc.contributor.authorMayfield, Rachel M
dc.contributor.authorHelms, Gregory
dc.contributor.authorGregorio, Carol C
dc.contributor.authorKostyukova, Alla S
dc.date.accessioned2016-12-07T02:01:28Z
dc.date.available2016-12-07T02:01:28Z
dc.date.issued2016-08-15
dc.identifier.citationThe N-terminal tropomyosin- and actin-binding sites are important for leiomodin 2's function. 2016, 27 (16):2565-75 Mol. Biol. Cellen
dc.identifier.issn1939-4586
dc.identifier.pmid27307584
dc.identifier.doi10.1091/mbc.E16-03-0200
dc.identifier.urihttp://hdl.handle.net/10150/621526
dc.description.abstractLeiomodin is a potent actin nucleator related to tropomodulin, a capping protein localized at the pointed end of the thin filaments. Mutations in leiomodin-3 are associated with lethal nemaline myopathy in humans, and leiomodin-2-knockout mice present with dilated cardiomyopathy. The arrangement of the N-terminal actin- and tropomyosin-binding sites in leiomodin is contradictory and functionally not well understood. Using one-dimensional nuclear magnetic resonance and the pointed-end actin polymerization assay, we find that leiomodin-2, a major cardiac isoform, has an N-terminal actin-binding site located within residues 43-90. Moreover, for the first time, we obtain evidence that there are additional interactions with actin within residues 124-201. Here we establish that leiomodin interacts with only one tropomyosin molecule, and this is the only site of interaction between leiomodin and tropomyosin. Introduction of mutations in both actin- and tropomyosin-binding sites of leiomodin affected its localization at the pointed ends of the thin filaments in cardiomyocytes. On the basis of our new findings, we propose a model in which leiomodin regulates actin poly-merization dynamics in myocytes by acting as a leaky cap at thin filament pointed ends.
dc.description.sponsorshipNational Institutes of Health [RO1GM081688, R01HL108625, R01HL123078, 1F31HL117520]en
dc.language.isoenen
dc.publisherAMER SOC CELL BIOLOGYen
dc.relation.urlhttp://www.molbiolcell.org/content/early/2016/06/13/mbc.E16-03-0200en
dc.rights© 2016 Ly, Moroz, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc -sa/3.0).en
dc.titleThe N-terminal tropomyosin- and actin-binding sites are important for leiomodin 2's function.en
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Sarver Mol Cardiovasc Res Program, Dept Cellular & Mol Meden
dc.identifier.journalMolecular biology of the cellen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-06-15T17:56:36Z
html.description.abstractLeiomodin is a potent actin nucleator related to tropomodulin, a capping protein localized at the pointed end of the thin filaments. Mutations in leiomodin-3 are associated with lethal nemaline myopathy in humans, and leiomodin-2-knockout mice present with dilated cardiomyopathy. The arrangement of the N-terminal actin- and tropomyosin-binding sites in leiomodin is contradictory and functionally not well understood. Using one-dimensional nuclear magnetic resonance and the pointed-end actin polymerization assay, we find that leiomodin-2, a major cardiac isoform, has an N-terminal actin-binding site located within residues 43-90. Moreover, for the first time, we obtain evidence that there are additional interactions with actin within residues 124-201. Here we establish that leiomodin interacts with only one tropomyosin molecule, and this is the only site of interaction between leiomodin and tropomyosin. Introduction of mutations in both actin- and tropomyosin-binding sites of leiomodin affected its localization at the pointed ends of the thin filaments in cardiomyocytes. On the basis of our new findings, we propose a model in which leiomodin regulates actin poly-merization dynamics in myocytes by acting as a leaky cap at thin filament pointed ends.


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