Molecular modeling of disease causing mutations in domain C1 of cMyBP-C

Cardiac myosin binding protein-C (cMyBP-C) is a multi-domain (C0-C10) protein that regulates heart muscle contraction through interaction with myosin, actin and other sarcomeric proteins. Several mutations of this protein cause familial hypertrophic cardiomyopathy (HCM). Domain C1 of cMyBP-C plays a...

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Bibliographic Details
Published in:	PloS one 2013-03, Vol.8 (3), p.e59206-e59206
Main Authors:	Gajendrarao, Poornima, Krishnamoorthy, Navaneethakrishnan, Kassem, Heba Sh, Moharem-Elgamal, Sarah, Cecchi, Franco, Olivotto, Iacopo, Yacoub, Magdi H
Format:	Article
Language:	eng
Subjects:	Actin Biological effects Biology Cardiac muscle Cardiomyopathy Cardiomyopathy, Hypertrophic, Familial - genetics Carrier Proteins - chemistry Carrier Proteins - genetics Charge distribution Computational Biology - methods Computer applications Crystal structure Crystallography, X-Ray Crystals Disease DNA Mutational Analysis Egypt Familial hypertrophic cardiomyopathy Genes Genomics Heart Heart diseases Humans Materials Science Medicine Models, Molecular Molecular Dynamics Simulation Molecular modelling Muscle contraction Muscle proteins Muscles Mutants Mutation Mutation, Missense - genetics Myosin Protein binding Protein interaction Protein Structure, Tertiary Proteins Static Electricity Structural integrity Structure Structure-function relationships Surface charge
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Summary:	Cardiac myosin binding protein-C (cMyBP-C) is a multi-domain (C0-C10) protein that regulates heart muscle contraction through interaction with myosin, actin and other sarcomeric proteins. Several mutations of this protein cause familial hypertrophic cardiomyopathy (HCM). Domain C1 of cMyBP-C plays a central role in protein interactions with actin and myosin. Here, we studied structure-function relationship of three disease causing mutations, Arg177His, Ala216Thr and Glu258Lys of the domain C1 using computational biology techniques with its available X-ray crystal structure. The results suggest that each mutation could affect structural properties of the domain C1, and hence it's structural integrity through modifying intra-molecular arrangements in a distinct mode. The mutations also change surface charge distributions, which could impact the binding of C1 with other sarcomeric proteins thereby affecting contractile function. These structural consequences of the C1 mutants could be valuable to understand the molecular mechanisms for the disease.
ISSN:	1932-6203 1932-6203