Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Poster Session II

32-POS Board 8 Bedside to Bench: Molecular Modeling of Double Mutation of cMyBP-C Resulting in Severe Phenotype Navaneethakrishnan Krishnamoorthy 1,3 , Poornima Gajendrarao 1,3 , Francesca Girolami 2 , Franco Cecchi 2 , Iacopo Olivotto 2 , Magdi Yacoub 1,3 . 1 Qatar Foundation, Doha, Doha, Qatar, 2 Careggi University Hospital, Florence, Florence, Italy, 3 Imperial College London, London, United Kingdom. The gene MYBPC3 encodes cardiac myosin binding protein-C (cMyBP-C), a multi-domain (C0- C10) protein. Mutations in the gene are one of the major factors for causing inherited hypertrophic cardiomyopathy (HCM). Here, we describe molecular modelling of a double mutation in cMyBP-C in a patient with severe phenotype of HCM and the mutations are in the complex C1(E258K)-motif-C2(E441K). The 3D structure for the motif was modelled. The complex C1-motif-C2 was constructed and both the double and single mutations were introduced in the complex. Molecular dynamics simulations were performed for 10ns for the complexes. The results showed that the E258K and E441K in isolation can predominantly affect the native domain as well as the nearby motif via conformational changes, when they exist together it resulted in an additive effect. These changes involved potentially important regions in the motif such as phosphorylation sites. The mutations also modified the inter-domain interface of C1- motif-C2 and altered the surface electrostatic properties. This study suggests that the double mutation in the regulatory N-terminal of cMyBP-C could interfere with the binding to neighbouring domains and with other sarcomeric proteins such as actin and myosin, thus explaining a putative mechanism for severe phenotype in our patient.

- 84 -