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lüll Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes Candasamy AJ; Haworth RS; Cuello F; Ibrahim M; Aravamudhan S; Kruger M; Holt MR; Terracciano CM; Mayr M; Gautel M; Avkiran MJ Biol Chem 2014[Jan]; 289 (3): 1282-93Telethonin (also known as titin-cap or t-cap) is a muscle-specific protein whose mutation is associated with cardiac and skeletal myopathies through unknown mechanisms. Our previous work identified cardiac telethonin as an interaction partner for the protein kinase D catalytic domain. In this study, kinase assays used in conjunction with MS and site-directed mutagenesis confirmed telethonin as a substrate for protein kinase D and Ca(2+)/calmodulin-dependent kinase II in vitro and identified Ser-157 and Ser-161 as the phosphorylation sites. Phosphate affinity electrophoresis and MS revealed endogenous telethonin to exist in a constitutively bis-phosphorylated form in isolated adult rat ventricular myocytes and in mouse and rat ventricular myocardium. Following heterologous expression in myocytes by adenoviral gene transfer, wild-type telethonin became bis-phosphorylated, whereas S157A/S161A telethonin remained non-phosphorylated. Nevertheless, both proteins localized predominantly to the sarcomeric Z-disc, where they partially replaced endogenous telethonin. Such partial replacement with S157A/S161A telethonin disrupted transverse tubule organization and prolonged the time to peak of the intracellular Ca(2+) transient and increased its variance. These data reveal, for the first time, that cardiac telethonin is constitutively bis-phosphorylated and suggest that such phosphorylation is critical for normal telethonin function, which may include maintenance of transverse tubule organization and intracellular Ca(2+) transients.|Amino Acid Substitution[MESH]|Animals[MESH]|Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics/metabolism[MESH]|Calcium/metabolism[MESH]|Cells, Cultured[MESH]|Connectin/genetics/*metabolism[MESH]|Heart Ventricles/cytology/metabolism[MESH]|Humans[MESH]|Male[MESH]|Mice[MESH]|Microtubules/genetics/metabolism[MESH]|Muscle Proteins/genetics/*metabolism[MESH]|Mutation, Missense[MESH]|Myocytes, Cardiac/cytology/*metabolism[MESH]|Phosphorylation/physiology[MESH]|Protein Kinase C/genetics/metabolism[MESH]|Rats[MESH]|Rats, Wistar[MESH]|Sarcomeres/genetics/metabolism[MESH] |