期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 64, 期 -, 页码 39-50出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2013.08.006
关键词
Cardiac function; Sarcomere; Phosphorylation; Cardiac myosin binding protein C
资金
- NIH [P01HL077101, P01HL059408, R01HL105924]
- Transatlantic Network of Excellence Program grant from Le Fondation Leducq
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; MD 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 MD mice showed pathology that was more severe than cMyBP-C nulls. DAA and MD 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. (C) 2013 Elsevier Ltd. All rights reserved.
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