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

Poornima Gajendrarao; Navaneethakrishnan Krishnamoorthy; Heba Sh Kassem; Sarah Moharem-Elgamal; Franco Cecchi; Iacopo Olivotto; Magdi H Yacoub

doi:10.1371/journal.pone.0059206

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

PLoS One. 2013;8(3):e59206. doi: 10.1371/journal.pone.0059206. Epub 2013 Mar 19.

Authors

Poornima Gajendrarao¹, Navaneethakrishnan Krishnamoorthy, Heba Sh Kassem, Sarah Moharem-Elgamal, Franco Cecchi, Iacopo Olivotto, Magdi H Yacoub

Affiliation

¹ Qatar Cardiovascular Research Center, Qatar Foundation, Doha, Qatar.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cardiomyopathy, Hypertrophic, Familial / genetics*
Carrier Proteins / chemistry
Carrier Proteins / genetics*
Computational Biology / methods
Crystallography, X-Ray
DNA Mutational Analysis
Egypt
Humans
Models, Molecular*
Molecular Dynamics Simulation
Mutation, Missense / genetics*
Protein Structure, Tertiary*
Static Electricity

Substances

Carrier Proteins
myosin-binding protein C

Grants and funding

This research was supported by Qatar Foundation through Qatar Cardiovascular research Center, Doha, Qatar and it was also supported by Magdi Yacoub Research Network, London, United Kingdom. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.