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Nanomechanical Phenotypes in Cardiac Myosin-Binding Protein C Mutants That Cause Hypertrophic Cardiomyopathy
Carmen Suay-Corredera1, Maria Rosaria Pricolo1,2, Diana Velázquez-Carreras1
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain.
Insights
Pathogenic mutations in cardiac myosin-binding protein C (cMyBP-C) can alter its nanomechanics, contributing to hypertrophic cardiomyopathy (HCM). These changes affect protein folding and stability, offering new insights into HCM development.
Area of Science:
- Biophysics
- Cardiovascular Biology
- Molecular Medicine
Background:
- Hypertrophic cardiomyopathy (HCM) is a myocardial disease often caused by mutations in sarcomeric proteins.
- Approximately 50% of HCM-related genetic variants affect cardiac myosin-binding protein C (cMyBP-C).
- Pathogenic mechanisms for many cMyBP-C mutations remain unclear, as they don't alter protein structure or stability.
Purpose of the Study:
- To investigate if pathogenic mutations in cMyBP-C perturb its nanomechanics.
- To determine if these nanomechanical changes compromise cMyBP-C's function as a mechanical tether in actomyosin filaments.
- To explore an alternative pathomechanism for HCM development linked to cMyBP-C nanomechanics.
Main Methods:
- Single-molecule atomic force spectroscopy was employed.
- Mechanical folding and unfolding transitions of cMyBP-C domains were quantified.
- Mutations associated with HCM (R495W, R502Q) were analyzed in comparison to wild-type and nonpathogenic variants.
Main Results:
- HCM-associated mutations R495W weakened cMyBP-C domains at forces below 40 pN.
- The R502Q mutant domains exhibited faster folding kinetics compared to wild-type.
- These nanomechanical alterations were specific to pathogenic variants, not observed in controls.
Conclusions:
- Nanomechanical changes in cMyBP-C, independent of structural stability, contribute to hypertrophic cardiomyopathy pathogenesis.
- Altered protein nanomechanics represent a potential common mechanism in various human pathologies involving mechanical proteins.
- This study highlights the importance of protein nanomechanics in understanding inherited cardiac diseases.
Abstract:
Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C domains targeted by HCM mutations that do not induce RNA splicing alterations or protein thermodynamic destabilization. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, nonpathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies.
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