Dynamics of the β-cardiac myosin auto-inhibited state explain cardiomyopathy pathogenesis
Abstract
Cardiac contractility requires precise regulation. A recently discovered form of regulation of cardiac contractility involves a β-cardiac myosin off-state, the Interacting-Heads Motif ( Car IHM). Despite its central role in cardiac physiology and disease, Car IHM structural dynamics remain poorly understood. Here, we integrate near-atomic resolution cryo-EM with all-atom molecular dynamics to characterize Car IHM in solution and in the context of the filament. We describe its conformational ensembles maintained by dynamic interfaces, and the stabilizing effect of the dilated cardiomyopathy mutation E525K, which limits S2 coiled-coil flexibility and impairs myosin activation. Intrinsically disordered regions of Car IHM and MyBP-C further modulate these dynamics. Our findings provide evidence for how Car IHM ensembles balance off/on states and anchor myosin heads in distinct thick filament environments. This integrated structural and dynamic approach enhances the understanding of thick filament regulation and facilitates predictions of the effects of genetic variants in inherited cardiomyopathies.
Related
- AL Cardiac Amyloidosis Mimicking Dilated Cardiomyopathy With Reduced Ejection Fraction and Absent Apical Sparing
- Wild-Type Transthyretin Amyloid Cardiomyopathy With Positive 18F-FDG/13N-Ammonia Cardiac Positron Emission Tomography
- The Dilated Cardiomyopathy E525K Mutation Stabilizes the Cardiac Myosin Interacting-Heads Motif While Activating the Isolated Motor Domain
- PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12
- Plasmodium falciparum putative Hsp90 functionally complements yeast Hsp90 and is inhibited in an isoform-specific manner
BibTeX
@article{auguin2026dynamics,
title = {{Dynamics of the β-cardiac myosin auto-inhibited state explain cardiomyopathy pathogenesis}},
author = {Daniel Auguin and Laurie Lannes and Carlos M Kikuti and Nour Ayoub and Marie Juillé and Stéphane Réty and Neha Nandwani and Divya Pathak and Kathleen Ruppel and James Spudich and Julien Robert-Paganin and Anne Houdusse},
journal = {Nature Communications},
year = {2026},
month = jun,
doi = {10.1038/s41467-026-73572-5},
url = {https://hal.science/hal-05765368v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Dynamics of the β-cardiac myosin auto-inhibited state explain cardiomyopathy pathogenesis
AU - Daniel Auguin
AU - Laurie Lannes
AU - Carlos M Kikuti
AU - Nour Ayoub
AU - Marie Juillé
AU - Stéphane Réty
AU - Neha Nandwani
AU - Divya Pathak
AU - Kathleen Ruppel
AU - James Spudich
AU - Julien Robert-Paganin
AU - Anne Houdusse
PY - 2026
DA - 2026/06/04
JO - Nature Communications
DO - 10.1038/s41467-026-73572-5
UR - https://hal.science/hal-05765368v1
AB - Cardiac contractility requires precise regulation. A recently discovered form of regulation of cardiac contractility involves a β-cardiac myosin off-state, the Interacting-Heads Motif ( Car IHM). Despite its central role in cardiac physiology and disease, Car IHM structural dynamics remain poorly understood. Here, we integrate near-atomic resolution cryo-EM with all-atom molecular dynamics to characterize Car IHM in solution and in the context of the filament. We describe its conformational ensembles maintained by dynamic interfaces, and the stabilizing effect of the dilated cardiomyopathy mutation E525K, which limits S2 coiled-coil flexibility and impairs myosin activation. Intrinsically disordered regions of Car IHM and MyBP-C further modulate these dynamics. Our findings provide evidence for how Car IHM ensembles balance off/on states and anchor myosin heads in distinct thick filament environments. This integrated structural and dynamic approach enhances the understanding of thick filament regulation and facilitates predictions of the effects of genetic variants in inherited cardiomyopathies.
SN - 2041-1723
SN - 2041-1723
ER -