Interaction of Cardiac Leiomodin with the Native Cardiac Thin Filament

Authors

Madison Little, Washington State University
Cristina M. Risi, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
Tania M. Larrinaga, University of Arizona
Mason D. Summers, Washington State University
Tyler Nguyen, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
Garry E. Smith Jr., Washington State University
Jennifer Atherton, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow
Carol C. Gregorio, Icahn School of Medicine at Mount Sinai
Alla S. Kostyukova, Washington State University
Vitold E. Galkin, Macon & Joan Brock Virginia Health Sciences at Old Dominion UniversityFollow

ORCID

0000-0002-3145-2072 (Risi), 0000-0003-1138-7565 (Galkin)

Document Type

Article

Publication Date

2025

DOI

10.1371/journal.pbio.3003027

Publication Title

PLoS Biology

Volume

23

Issue

1

Pages

e3003027 (1-21)

Abstract

Every heartbeat depends on cyclical contraction-relaxation produced by the interactions between myosin-containing thick and actin-based thin filaments (TFs) arranged into a crystalline-like lattice in the cardiac sarcomere. Therefore, the maintenance of thin filament length is crucial for myocardium function. The thin filament is comprised of an actin backbone, the regulatory troponin complex and tropomyosin that controls interactions between thick and thin filaments. Thin filament length is controlled by the tropomodulin family of proteins; tropomodulin caps pointed ends of thin filaments, and leiomodin (Lmod) promotes elongation of thin filaments by a “leaky-cap” mechanism. The broader distribution of Lmod on the thin filament implied to the possibility of its interaction with the sides of thin filaments. Here, we use biochemical and structural approaches to show that cardiac Lmod (Lmod2) binds to a specific region on the native cardiac thin filament in a Ca²⁺-dependent manner. We demonstrate that Lmod2’s unique C-terminal extension is required for binding to the thin filament actin backbone and suggest that interactions with the troponin complex assist Lmod2’s localization on the surface of thin filaments. We propose that Lmod2 regulates the length of cardiac thin filaments in a working myocardium by protecting newly formed thin filament units during systole and promoting actin polymerization at thin filament pointed ends during diastole.

Rights

© 2025 Little et al.

This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability

Article states: "Cryo-EM maps for relaxed and activated cTFs decorated with Lmod2 were deposited in the Electron Microscopy Data Bank (www.ebi.ac.uk/pdbe/emdb) with accession codes EMD-47712 and EMD-47714, respectively."

Original Publication Citation

Little, M., Risi, C. M., Larrinaga, T. M., Summers, M., Nguyen, T., Smith, G. E., Jr., Atherton, J., Gregorio, C. C., Kostyukova, A. S., & Galkin, V. E. (2025). Interaction of cardiac leiomodin with the native cardiac thin filament. PLoS Biology, 23(1), 1-21, Article e3003027. https://doi.org/10.1371/journal.pbio.3003027

Repository Citation

Little, M., Risi, C. M., Larrinaga, T. M., Summers, M., Nguyen, T., Smith, G. E., Jr., Atherton, J., Gregorio, C. C., Kostyukova, A. S., & Galkin, V. E. (2025). Interaction of cardiac leiomodin with the native cardiac thin filament. PLoS Biology, 23(1), 1-21, Article e3003027. https://doi.org/10.1371/journal.pbio.3003027