The HCM-causing Y235S cMyBPC mutation accelerates contractile function by altering C1 domain structure.

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Genetic Basis of Heart Disease

Background:

• Mutations in cardiac myosin binding protein C (cMyBPC) are a primary genetic cause of hypertrophic cardiomyopathy (HCM).
• While various cMyBPC mutations are known, the functional impact of missense mutations, such as Y235S, remains less understood.
• The Y235S substitution in cMyBPC is strongly associated with HCM development.

Purpose of the Study:

• To investigate the functional and structural consequences of the HCM-associated Y235S missense mutation in cMyBPC.
• To elucidate the molecular mechanisms by which the Y235S mutation leads to cardiac dysfunction.

Main Methods:

• Utilized viral transfection to express wild-type (WT) and Y235S cMyBPC in cMyBPC null mouse myocardium.
• Performed mechanical experiments on detergent-skinned myocardium to assess contractile properties and calcium sensitivity.
• Employed molecular dynamics simulations (MDS) to analyze structural changes in the cMyBPC C1 domain.

Main Results:

• Y235S cMyBPC was correctly expressed and integrated into the cardiac sarcomere, ruling out haploinsufficiency or poison peptide mechanisms.
• Myocardium expressing Y235S cMyBPC exhibited hypercontractile behavior, characterized by faster cross-bridge kinetics and heightened calcium sensitivity.
• MDS revealed that the Y235S mutation alters intramolecular interactions, surface conformation, and electrostatic potential within the cMyBPC C1 domain.

Conclusions:

• The Y235S mutation directly impacts the structural and functional properties of the cMyBPC C1 domain.
• These molecular alterations likely disrupt ligand-binding interactions, leading to hypercontractile cross-bridge behavior.
• This aberrant cardiac function contributes to the pathogenesis of cardiac hypertrophy and dysfunction observed in HCM.