Hypertrophic cardiomyopathy-linked variants of cardiac myosin-binding protein C3 display altered molecular properties and actin interaction.

Autor:	Da'as SI; Translational Medicine, Sidra Medicine, Doha, Qatar.; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar., Fakhro K; Translational Medicine, Sidra Medicine, Doha, Qatar.; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.; Weill Cornell Medical College, Doha, Qatar., Thanassoulas A; National Center for Scientific Research 'Demokritos', Aghia Paraskevi, Greece., Krishnamoorthy N; Translational Medicine, Sidra Medicine, Doha, Qatar.; Heart Science Centre, National Heart and Lung Institute, Imperial College, London, U.K., Saleh A; College of Medicine, Member of QU Health, Qatar University, Doha, Qatar., Calver BL; College of Biomedical & Life Sciences, Cardiff University, Cardiff, U.K., Safieh-Garabedian B; College of Medicine, Member of QU Health, Qatar University, Doha, Qatar., Toft E; College of Medicine, Member of QU Health, Qatar University, Doha, Qatar., Nounesis G; National Center for Scientific Research 'Demokritos', Aghia Paraskevi, Greece., Lai FA; College of Medicine, Member of QU Health, Qatar University, Doha, Qatar.; College of Biomedical & Life Sciences, Cardiff University, Cardiff, U.K.; Biomedical Research Center, Qatar University, Doha, Qatar., Nomikos M; College of Medicine, Member of QU Health, Qatar University, Doha, Qatar mixosn@yahoo.com mnomikos@qu.edu.qa.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2018 Dec 14; Vol. 475 (24), pp. 3933-3948. Date of Electronic Publication: 2018 Dec 14.
DOI:	10.1042/BCJ20180685
Abstrakt:	The most common inherited cardiac disorder, hypertrophic cardiomyopathy (HCM), is characterized by thickening of heart muscle, for which genetic mutations in cardiac myosin-binding protein C3 ( c-MYBPC3 ) gene, is the leading cause. Notably, patients with HCM display a heterogeneous clinical presentation, onset and prognosis. Thus, delineating the molecular mechanisms that explain how disparate c-MYBPC3 variants lead to HCM is essential for correlating the impact of specific genotypes on clinical severity. Herein, five c-MYBPC3 missense variants clinically associated with HCM were investigated; namely V1 (R177H), V2 (A216T), V3 (E258K), V4 (E441K) and double mutation V5 (V3 + V4), all located within the C1 and C2 domains of MyBP-C, a region known to interact with sarcomeric protein, actin. Injection of the variant complementary RNAs in zebrafish embryos was observed to recapitulate phenotypic aspects of HCM in patients. Interestingly, V3- and V5-cRNA injection produced the most severe zebrafish cardiac phenotype, exhibiting increased diastolic/systolic myocardial thickness and significantly reduced heart rate compared with control zebrafish. Molecular analysis of recombinant C0-C2 protein fragments revealed that c-MYBPC3 variants alter the C0-C2 domain secondary structure, thermodynamic stability and importantly, result in a reduced binding affinity to cardiac actin. V5 (double mutant), displayed the greatest protein instability with concomitant loss of actin-binding function. Our study provides specific mechanistic insight into how c-MYBPC3 pathogenic variants alter both functional and structural characteristics of C0-C2 domains leading to impaired actin interaction and reduced contractility, which may provide a basis for elucidating the disease mechanism in HCM patients with c- MYBPC3 mutations. (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu