Functional dissection of myosin binding protein C phosphorylation. J Mol Cell Cardiol 2013 Nov;64:39-50
Date
09/05/2013Pubmed ID
24001940Pubmed Central ID
PMC3847820DOI
10.1016/j.yjmcc.2013.08.006Scopus ID
2-s2.0-84884328229 (requires institutional sign-in at Scopus site) 20 CitationsAbstract
Cardiac myosin binding protein C (cMyBP-C) phosphorylation is differentially regulated in the normal heart and during disease development. Our objective was to examine in detail three phosphorylatable sites (Ser-273, Ser-282, and Ser-302) present in the protein's cardiac-specific sequences, as these residues are differentially and reversibly phosphorylated during normal and abnormal cardiac function. Three transgenic lines were generated: DAA, which expressed cMyBP-C containing Asp-273, Ala-282, and Ala-302, in which a charged amino acid was placed at residue 273 and the remaining two sites rendered nonphosphorylatable by substituting alanines for the two serines; AAD containing Ala-273, Ala-282, and Asp-302, in which aspartate was placed at residue 302 and the remaining two sites rendered nonphosphorylatable; and SDS containing Ser-273, Asp-282, and Ser-302. These mice were compared to mice constructed previously along similar lines: wild type, in which normal cMyBP-C is transgenically expressed, AllP-, in which alanines were substituted and ADA mice as well. DAA and AAD mice showed pathology that was more severe than cMyBP-C nulls. DAA and AAD animals exhibited left ventricular chamber dilation, interstitial fibrosis, irregular cardiac rhythm and sudden cardiac death. Our results define the effects of the sites' post-translational modifications on cMyBP-C functionality and together, give a comprehensive picture of the potential consequences of site-specific phosphorylation. Ser-282 is a key residue in controlling S2 interaction with the thick and thin filaments. The new DAA and AAD constructs show that phosphorylation at one site in the absence of the ability to phosphorylate the other sites, depending upon the particular residues involved, can lead to severe cardiac remodeling and dysfunction.
Author List
Gupta MK, Gulick J, James J, Osinska H, Lorenz JN, Robbins JMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Cardiomyopathy, Dilated
Carrier Proteins
Codon
Echocardiography
Electrocardiography
Fibrosis
Hemodynamics
Mice
Mice, Transgenic
Molecular Sequence Data
Mutation
Myocardium
Phosphorylation
Sequence Alignment
Serine
