S‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure
S‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure
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Sâ 谷胱甘肽修饰会损害人心力衰竭中心肌肌球蛋白结合蛋白 C 的磷酸调节和功能
DOI：
10.1096/fj.201500048
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Cuello F
中科院分区：
文献类型：
--
作者：
Stathopoulou K;Wittig I;Heidler J;Piasecki A;Richter F;Diering S;van der Velden J;Buck F;Donzelli S;Schroeder E;Wijnker P;Voigt N;Dobrev D;Sadayappan S;Eschenhagen T;Carrier L;Eaton P;Cuello F
心肌肌球蛋白结合蛋白C（cMyBP-C）调节肌动蛋白-肌球蛋白相互作用，从而调节心肌细胞的收缩和舒张。这种生理功能由cMyBP-C磷酸化调节。在我们的研究中，与非衰竭供体相比，扩张型或缺血性心肌病患者心室组织中位点特异性cMyBP-C磷酸化的减少与S-谷胱甘肽化的增加相一致。我们使用氧化还原蛋白质组学，以确定组成和疾病特异性的S-谷胱甘肽在供体和患者样本中的cMyBP-C位点，分别。其中，在肌球蛋白S2相互作用结构域C1-M-C2内的调节磷酸化位点附近的半胱氨酸簇被鉴定，并在患者中显示出增强的S-谷胱甘肽化。在体外，重组cMyBP-C C1-M-C2的S-谷胱甘肽化主要发生在Cys 249处，这减弱了蛋白激酶的磷酸化。暴露于谷胱甘肽二硫化物诱导cMyBP-C S-谷胱甘肽化，这在功能上减慢了野生型心室肌细胞中Ca 2+激活力发展的动力学，但不是Mybpc 3靶向敲除小鼠的动力学。这些氧化事件消除了蛋白激酶介导的cMyBP-C磷酸化，因此可能有助于减少其磷酸化和在人类心力衰竭中观察到的收缩功能障碍。Stathopoulou，K.，维蒂希岛，Heidler，J.，Piasecki，A.，Richter，F.，Diering，S.，货车德尔费尔登，J.，巴克，F.，Donzelli，S.，Schröder，E.，Wijnker，P. J. M.，Voigt，N.，Dobrev，D.，Sadayappan，S.，Eschenhagen，T.，开利湖，Eaton，P.，Cuello，F. S-谷胱甘肽损伤心力衰竭患者心肌肌球蛋白结合蛋白C的磷酸化调节和功能
Cardiac myosin-binding protein C (cMyBP-C) regulates actin–myosin interaction and thereby cardiac myocyte contraction and relaxation. This physiologic function is regulated by cMyBP-C phosphorylation. In our study, reduced site-specific cMyBP-C phosphorylation coincided with increased S-glutathiolation in ventricular tissue from patients with dilated or ischemic cardiomyopathy compared to nonfailing donors. We used redox proteomics, to identify constitutive and disease-specific S-glutathiolation sites in cMyBP-C in donor and patient samples, respectively. Among those, a cysteine cluster in the vicinity of the regulatory phosphorylation sites within the myosin S2 interaction domain C1-M-C2 was identified and showed enhanced S-glutathiolation in patients. In vitro S-glutathiolation of recombinant cMyBP-C C1-M-C2 occurred predominantly at Cys249, which attenuated phosphorylation by protein kinases. Exposure to glutathione disulfide induced cMyBP-C S-glutathiolation, which functionally decelerated the kinetics of Ca2+-activated force development in ventricular myocytes from wild-type, but not those from Mybpc3-targeted knockout mice. These oxidation events abrogate protein kinase–mediated phosphorylation of cMyBP-C and therefore potentially contribute to the reduction of its phosphorylation and the contractile dysfunction observed in human heart failure.—Stathopoulou, K., Wittig, I., Heidler, J., Piasecki, A., Richter, F., Diering, S., van der Velden, J., Buck, F., Donzelli, S., Schröder, E., Wijnker, P. J. M., Voigt, N., Dobrev, D., Sadayappan, S., Eschenhagen, T., Carrier, L., Eaton, P., Cuello, F. S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure.
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影响因子：
2.7
作者：
Hamdani, Nazha;Borbely, Attila;Veenstra, Sophie P. G. R.;Kooij, Viola;Vrydag, Wim;Zaremba, Ruud;dos Remedios, Cris;Niessen, Hans W. M.;Michel, Martin C.;Paulus, Walter J.;Stienen, Ger J. M.;van der Velden, Jolanda
通讯作者：
van der Velden, Jolanda
GSK3&bgr; 磷酸化心脏肌球蛋白结合蛋白 C 富含脯氨酸丙氨酸的区域中新发现的位点并改变人类的跨桥循环动力学：短通讯
影响因子：
20.1
作者：
D. Kuster;V. Sequeira;A. Najafi;N. Boontje;P. Wijnker;E. R. Witjas;Steven B Marston;C. D. dos Remedios;L. Carrier;Jeroen A. A. Demmers;C. Redwood;S. Sadayappan;J. van der Velden
通讯作者：
J. van der Velden
影响因子：
3.4
作者：
Lecarpentier, Yves;Vignier, Nicolas;Coirault, Catherine
通讯作者：
Coirault, Catherine
影响因子：
56.9
作者：
Xu, L;Eu, JP;Stamler, JS
通讯作者：
Stamler, JS
影响因子：
4.8
作者：
Seidel, Susanne A. I.;Dijkman, Patricia M.;Lea, Wendy A.;van den Bogaart, Geert;Jerabek-Willemsen, Moran;Lazic, Ana;Joseph, Jeremiah S.;Srinivasan, Prakash;Baaske, Philipp;Simeonov, Anton;Katritch, Ilia;Melo, Fernando A.;Ladbury, John E.;Schreiber, Gideon;Watts, Anthony;Braun, Dieter;Duhr, Stefan
通讯作者：
Duhr, Stefan