title: Molecular modeling of disease causing mutations in domain C1 of cMyBP-C.
abstract: 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.
authors.affiliation: Qatar Cardiovascular Research Center, Qatar Foundation, Doha, Qatar.
authors.forename: Poornima
authors.initials: P
authors.lastname: Gajendrarao
authors.forename: Navaneethakrishnan
authors.initials: N
authors.lastname: Krishnamoorthy
authors.forename: Heba Sh
authors.initials: HSh
authors.lastname: Kassem
authors.forename: Sarah
authors.initials: S
authors.lastname: Moharem-Elgamal
authors.forename: Franco
authors.initials: F
authors.lastname: Cecchi
authors.forename: Iacopo
authors.initials: I
authors.lastname: Olivotto
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
mesh_terms: D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D004534:Egypt; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense / Q000235:genetics*; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C