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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Article numbere59206
JournalPLoS One
Volume8
Issue number3
DOIs
Publication statusPublished - 19 Mar 2013

Fingerprint

Cardiac Myosins
Molecular modeling
myosin
binding proteins
mutation
Mutation
Myosins
Proteins
proteins
actin
Actins
Familial Hypertrophic Cardiomyopathy
muscle contraction
cardiomyopathy
Charge distribution
Structural integrity
structure-activity relationships
Surface charge
Muscle Contraction
crystal structure

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Gajendrarao, P., Krishnamoorthy, N., Kassem, H. S., Moharem-Elgamal, S., Cecchi, F., Olivotto, I., & Yacoub, M. H. (2013). Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C. PLoS One, 8(3), [e59206]. https://doi.org/10.1371/journal.pone.0059206

Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C. / Gajendrarao, Poornima; Krishnamoorthy, Navaneethakrishnan; Kassem, Heba Sh; Moharem-Elgamal, Sarah; Cecchi, Franco; Olivotto, Iacopo; Yacoub, Magdi H.

In: PLoS One, Vol. 8, No. 3, e59206, 19.03.2013.

Research output: Contribution to journalArticle

Gajendrarao, P, Krishnamoorthy, N, Kassem, HS, Moharem-Elgamal, S, Cecchi, F, Olivotto, I & Yacoub, MH 2013, 'Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C', PLoS One, vol. 8, no. 3, e59206. https://doi.org/10.1371/journal.pone.0059206
Gajendrarao P, Krishnamoorthy N, Kassem HS, Moharem-Elgamal S, Cecchi F, Olivotto I et al. Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C. PLoS One. 2013 Mar 19;8(3). e59206. https://doi.org/10.1371/journal.pone.0059206
Gajendrarao, Poornima ; Krishnamoorthy, Navaneethakrishnan ; Kassem, Heba Sh ; Moharem-Elgamal, Sarah ; Cecchi, Franco ; Olivotto, Iacopo ; Yacoub, Magdi H. / Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C. In: PLoS One. 2013 ; Vol. 8, No. 3.
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