The N-terminal tropomyosin- and actin-binding sites are important for leiomodin 2's function

Thu Lya, Natalia Moroz, Christopher T. Pappas, Stefanie M. Novak, Dmitri Tolkatchev, Dayton Wooldridge, Rachel M. Mayfield, Gregory Helms, Carol C. Gregorio, Alla S. Kostyukova

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Leiomodin 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 polymerization dynamics in myocytes by acting as a leaky cap at thin filament pointed ends.

Original languageEnglish (US)
Pages (from-to)2565-2575
Number of pages11
JournalMolecular biology of the cell
Volume27
Issue number16
DOIs
StatePublished - Aug 15 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Lya, T., Moroz, N., Pappas, C. T., Novak, S. M., Tolkatchev, D., Wooldridge, D., Mayfield, R. M., Helms, G., Gregorio, C. C., & Kostyukova, A. S. (2016). The N-terminal tropomyosin- and actin-binding sites are important for leiomodin 2's function. Molecular biology of the cell, 27(16), 2565-2575. https://doi.org/10.1091/mbc.E16-03-0200