Hypertrophic cardiomyopathy mutations Y115H and E497D disrupt the folded-back state of human β-cardiac myosin allosterically

Neha Nandwani, Debanjan Bhowmik, Camille Glaser, Matthew Carter Childers, Rama Reddy Goluguri, Aminah Dawood, Michael Regnier, Anne Houdusse, James A. Spudich () and Kathleen M. Ruppel ()
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Neha Nandwani: Stanford University School of Medicine
Debanjan Bhowmik: Stanford University School of Medicine
Camille Glaser: PSL Research University
Matthew Carter Childers: University of Washington
Rama Reddy Goluguri: Stanford University School of Medicine
Aminah Dawood: Stanford University School of Medicine
Michael Regnier: University of Washington
Anne Houdusse: PSL Research University
James A. Spudich: Stanford University School of Medicine
Kathleen M. Ruppel: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract At the molecular level, clinical hypercontractility associated with many hypertrophic cardiomyopathy (HCM)-causing mutations in β-cardiac myosin appears to be driven by their disruptive effect on the energy-conserving, folded-back ‘OFF’-state of myosin, which results in increased number of heads free to interact with actin and produce force. While many characterized mutations likely act by directly perturbing intramolecular interfaces stabilizing the OFF-state, others may function allosterically by altering conformational states of the myosin motor. We investigate two such allosteric HCM mutations, Y115H (Transducer) and E497D (Relay helix), which do not directly contact OFF-state interfaces. Biochemical analyses and high-resolution crystallography reveal that both mutations increase active myosin head availability likely by destabilizing the pre-powerstroke conformation required for OFF-state formation. We propose that destabilization of the folded-back state of myosin, either directly or allosterically, represents a common molecular mechanism underlying hypercontractility in HCM across a broader spectrum of pathogenic mutations than previously recognized.

Date: 2025
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DOI: 10.1038/s41467-025-63816-1

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