S ‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure
| Autor: | Angelika Piasecki, Florian Richter, Sonia Donzelli, Friederike Cuello, Dobromir Dobrev, Sakthivel Sadayappan, Juliana Heidler, Niels Voigt, Lucie Carrier, Paul J.M. Wijnker, Jolanda van der Velden, Thomas Eschenhagen, Konstantina Stathopoulou, Ilka Wittig, Simon Diering, Friedrich Buck, Philip Eaton, Ewald Schröder |
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| Přispěvatelé: | Physiology, ICaR - Heartfailure and pulmonary arterial hypertension |
| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Heart Ventricles Medizin Biochemistry Research Communication Mice Young Adult 03 medical and health sciences chemistry.chemical_compound Myosin Genetics medicine Animals Humans Phosphorylation Molecular Biology Heart Failure Mice Knockout business.industry Kinase Binding protein Cardiovascular Agents Middle Aged medicine.disease Glutathione Cell biology 030104 developmental biology Gene Expression Regulation chemistry Heart failure Knockout mouse Immunology Cardiovascular agent Glutathione disulfide Female Carrier Proteins business Oxidation-Reduction Biotechnology |
| Zdroj: | Stathopoulou, K, Wittig, I, Heidler, J, Piasecki, A, Richter, F, Diering, S, van der Velden, J, Buck, F, Donzelli, S, Schroder, E, Wijnker, P J M, Voigt, N, Dobrev, D, Sadayappan, S, Eschenhagen, T, Carrier, L, Eaton, P & Cuello, F 2016, ' S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure ', FASEB Journal, vol. 30, no. 5, pp. 1849-1864 . https://doi.org/10.1096/fj.201500048 FASEB Journal, 30(5), 1849-1864. FASEB |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | 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 Cys(249), which attenuated phosphorylation by protein kinases. Exposure to glutathione disulfide induced cMyBP-C S-glutathiolation, which functionally decelerated the kinetics of Ca(2+)-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. |
| Databáze: | OpenAIRE |
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