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TitleDynamics of the β-cardiac myosin auto-inhibited state explain cardiomyopathy pathogenesis.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJun 4, 2026
AuthorsDaniel Auguin / Laurie Lannes / Carlos Kikuti / Nour Ayoub / Marie Juillé / Stéphane Réty / Neha Nandwani / Divya Pathak / Kathleen M Ruppel / James A Spudich / Julien Robert-Paganin / Anne Houdusse /
PubMed AbstractCardiac contractility requires precise regulation. A recently discovered form of regulation of cardiac contractility involves a β-cardiac myosin off-state, the Interacting-Heads Motif (IHM). Despite ...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 (IHM). Despite its central role in cardiac physiology and disease, IHM structural dynamics remain poorly understood. Here, we integrate near-atomic resolution cryo-EM with all-atom molecular dynamics to characterize 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 IHM and MyBP-C further modulate these dynamics. Our findings provide evidence for how 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.
External linksNat Commun / PubMed:42243087
MethodsEM (single particle)
Resolution3.02 - 3.8 Å
Structure data

56106

9tpj

EMDB-56106, PDB-9tpj:
Human Cardiac Interacting Heads Motif, E525K mutant
Method: EM (single particle) / Resolution: 3.02 Å

56107

9tpk

EMDB-56107, PDB-9tpk:
Human Cardiac Interacting Heads Motif, Conformation B
Method: EM (single particle) / Resolution: 3.8 Å

56108

9tpl

EMDB-56108, PDB-9tpl:
Human Cardiac Interacting Heads Motif, Conformation A
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-PO4:
PHOSPHATE ION

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMOTOR PROTEIN / Cardiac / myosin / thick filament / interacting-heads motif / IHM / beta-cardiac myosin / E525K

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