Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
J Mol Cell Cardiol. 2012 May;52(5):1145-54. doi: 10.1016/j.yjmcc.2012.01.006. Epub 2012 Jan 17.
Cardiac myosin binding protein C (cMyBP-C) is a myofibrillar protein important for normal myocardial contractility and stability. In mutated form it can cause cardiomyopathy and heart failure. cMyBP-C appears to have separate regions for different functions. Three phosphorylation sites near the N terminus modulate contractility by their effect on both the kinetics of contraction and the binding site of the N-terminus. The C terminal region binds to myosin rods and stabilizes thick filament structure. The aim of the study reported here was to test whether cMyBPC is important in producing the structural and functional changes that result from ischemia/reperfusion. In this study the sequential changes in cMyBP-C, contractility, and thick filament structure following dephosphorylation of cMyBP-C associated with ischemia and reperfusion have been studied in biopsied specimens from chronically instrumented dogs. One and two dimensional electrophoresis, electron microscopy and immunocytochemistry with multiple antibodies generated against different domains in cMyBP-C have been used to follow structural changes in cMyBP-C. Ischemia produced dephosphorylation of cMyBP-C. Subsequent reperfusion released the dephosphorylated cMyBP-C from myofibrils and activated proteolysis of the cytoplasmic cMyBP-C. This in turn leads to increased vulnerability of cMyBP-C to proteolysis and increased degradation of thick filaments. The state of cMyBP-C appears to be closely related to phosphorylation and dephosphorylation of serine 282. In the absence of the stabilizing action of cMyBP-C either as a consequence of genetic mutation or dephosphorylation, premature degradation of thick filaments occurs and is accompanied by persistent contractile dysfunction.
心肌肌球蛋白结合蛋白 C（cMyBP-C）是一种肌原纤维蛋白，对正常心肌收缩性和稳定性很重要。突变形式可导致心肌病和心力衰竭。cMyBP-C 似乎具有不同功能的分离区域。N 端附近的三个磷酸化位点通过影响收缩的动力学和 N 端结合位点来调节收缩性。C 端区域与肌球蛋白杆结合并稳定粗丝结构。本研究旨在测试 cMyBPC 是否对缺血/再灌注引起的结构和功能变化很重要。在这项研究中，通过对慢性仪器化犬活检标本进行研究，研究了与缺血和再灌注相关的 cMyBP-C 去磷酸化后 cMyBP-C、收缩性和粗丝结构的顺序变化。已使用一维和二维电泳、电子显微镜和针对 cMyBP-C 不同结构域生成的多克隆抗体免疫细胞化学来跟踪 cMyBP-C 的结构变化。缺血导致 cMyBP-C 去磷酸化。随后的再灌注使去磷酸化的 cMyBP-C 从肌原纤维中释放出来，并激活细胞质 cMyBP-C 的蛋白水解。这反过来又导致 cMyBP-C 对蛋白水解的易感性增加和粗丝降解增加。cMyBP-C 的状态似乎与丝氨酸 282 的磷酸化和去磷酸化密切相关。在缺乏 cMyBP-C 的稳定作用的情况下（无论是由于基因突变还是去磷酸化），粗丝会过早降解，并伴有持续的收缩功能障碍。
