Hypertrophic cardiomyopathy (HCM) is an inherent heart disease that dysregulate cardiac muscle contraction and several mutations in sarcomeric proteins are reported to be associated with HCM. Recently, in Egypt, we identified three disease causing mutations in cardiac myosin binding protein C (cMyBP-C), which is one of the sarcomeric proteins with multiple-domains (C0-C10). However, structure-function relationship for the mechanism of disease is largely unknown. Here, we describe structural consequences of the three HCM causing mutations, Arg177His, Ala216Thr and Glu258Lys, in domain C1 using molecular modeling techniques (Poornima et al., in press, PLOS ONE). Molecular dynamics simulations and stability analyses showed that the mutations affect the following structural properties of domain C1 i) rigidity, ii) intra-molecular interactions, iii) secondary structural elements and iv) surface electrostatics. The described structural changes (Figure) in domain C1 could distract binding of cMyBP-C to other sarcomeric proteins such as actin and/or myosin and thereby influence Ca2+ signalling and energy supply for contractile function to produce energy depletion. This study provides possible explanations to understand the relationship between structural change and molecular mechanism of the disease.
37th Congress of IUPS (Birmingham, UK) (2013) Proc 37th IUPS, PCA056
Poster Communications: A molecular modeling approach for understanding mechanism of disease causing mutations in domain C1 of cardiac myosin binding protein C
N. Krishnamoorthy1, P. Gajendra Rao1, H. S. Kassem2, S. Moharem-Elgamal2, F. Cecchi3, I. Olivotto3, M. H. Yacoub1,4
1. Qatar Cardiovascular Research Center, Qatar Foundation, Doha, Qatar. 2. BA-HCM National Programme, Aswan Heart Centre, Aswan, Egypt. 3. Referral Center for Myocardial Diseases, Careggi University Hospital, Florence, Italy. 4. National Heart and Lung Institute, Imperial College London, London, United Kingdom.
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