Posttranslational modifications of titin from cardiac muscle: how, where, and what for?
| Autor: | Franziska Koser, Christine M Loescher, Wolfgang A. Linke |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Sarcomeres
0301 basic medicine Force generation animal structures Phosphorylation sites oxidation heart disease macromolecular substances Biochemistry Sarcomere 03 medical and health sciences Vascular Stiffness 0302 clinical medicine State‐of‐the‐Art Review medicine oxidative stress Humans Myocyte Connectin Myocytes Cardiac Molecular Biology biology phosphorylation Chemistry Myocardium protein phosphatase Cardiac muscle Human heart cytoskeleton protein kinase Heart Cell Biology musculoskeletal system Cell biology 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis cardiovascular system biology.protein Phosphorylation elasticity Titin Oxidation-Reduction Protein Processing Post-Translational tissues |
| Zdroj: | The Febs Journal |
| ISSN: | 1742-4658 1742-464X |
| DOI: | 10.1111/febs.14854 |
| Popis: | Titin is a giant elastic protein expressed in the contractile units of striated muscle cells, including the sarcomeres of cardiomyocytes. The last decade has seen enormous progress in our understanding of how titin molecular elasticity is modulated in a dynamic manner to help cardiac sarcomeres adjust to the varying hemodynamic demands on the heart. Crucial events mediating the rapid modulation of cardiac titin stiffness are post‐translational modifications (PTMs) of titin. In this review, we first recollect what is known from earlier and recent work on the molecular mechanisms of titin extensibility and force generation. The main goal then is to provide a comprehensive overview of current insight into the relationship between titin PTMs and cardiomyocyte stiffness, notably the effect of oxidation and phosphorylation of titin spring segments on titin stiffness. A synopsis is given of which type of oxidative titin modification can cause which effect on titin stiffness. A large part of the review then covers the mechanically relevant phosphorylation sites in titin, their location along the elastic segment, and the protein kinases and phosphatases known to target these sites. We also include a detailed coverage of the complex changes in phosphorylation at specific titin residues, which have been reported in both animal models of heart disease and in human heart failure, and their correlation with titin‐based stiffness alterations. Knowledge of the relationship between titin PTMs and titin elasticity can be exploited in the search for therapeutic approaches aimed at softening the pathologically stiffened myocardium in heart failure patients. Titin is a giant elastic protein expressed in the contractile units of striated muscle cells, including cardiomyocytes. Rapid modulation of cardiac titin stiffness can be mediated through post‐translational modifications of titin, including oxidation and phosphorylation. This review notably details mechanically relevant phosphorylation sites in titin, their location, and the protein kinases and phosphatases known to target these sites. We include how titin phosphorylation correlates with titin‐based stiffness in heart failure. |
| Databáze: | OpenAIRE |
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