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Abstract

The cardiac muscle contraction is regulated by a set of proteins known as sarcomeric proteins, which are components of thick and thin filaments. Mutation in these proteins especially cardiac myosin binding protein-C, a multi-domain (C0-C10) protein, is one of the major causes of hypertrophic cardiomyopathy (HCM). However, structure-function relationship of this protein is unclear. Mutation E258K, which is located in the C-terminal of domain C1, has been shown to be associated with HCM in Egypt. Hence, the purpose of the study was to understand the molecular basis of this missense mutation. Molecular modelling study was performed using the available crystal structure of the domain C1. Here, we have carried out molecular dynamic simulations for both WT and E258K for 10 ns, and the structures that showed major changes were considered for further analyses. Our results suggest that the mutation can change the local structural stability through altering a series of intramolecular interactions. Moreover, as the mutation results in replacement of a negative amino acid by a positive one, thus, it affects the surface electrostatic properties of the domain (Figure). Hence, it might interfere with the binding to neighbouring domains and with the other sarcomeric proteins such as actin and myosin. E258K appears to affect the structural integrity of the domain C1 both directly and indirectly. It is hoped that these findings can help to understand the molecular mechanism of the disease.

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/content/papers/10.5339/qfarf.2012.BMO12
2012-10-01
2020-09-25
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http://instance.metastore.ingenta.com/content/papers/10.5339/qfarf.2012.BMO12
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