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Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes

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Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes. / Candasamy, Alexandra J; Haworth, Robert S; Cuello, Friederike; Ibrahim, Michael; Aravamudhan, Sriram; Krüger, Marcus; Holt, Mark R; Terracciano, Cesare M N; Mayr, Manuel; Gautel, Mathias; Avkiran, Metin.

In: J BIOL CHEM, Vol. 289, No. 3, 17.01.2014, p. 1282-1293.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Candasamy, AJ, Haworth, RS, Cuello, F, Ibrahim, M, Aravamudhan, S, Krüger, M, Holt, MR, Terracciano, CMN, Mayr, M, Gautel, M & Avkiran, M 2014, 'Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes', J BIOL CHEM, vol. 289, no. 3, pp. 1282-1293. https://doi.org/10.1074/jbc.M113.479030

APA

Candasamy, A. J., Haworth, R. S., Cuello, F., Ibrahim, M., Aravamudhan, S., Krüger, M., Holt, M. R., Terracciano, C. M. N., Mayr, M., Gautel, M., & Avkiran, M. (2014). Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes. J BIOL CHEM, 289(3), 1282-1293. https://doi.org/10.1074/jbc.M113.479030

Vancouver

Candasamy AJ, Haworth RS, Cuello F, Ibrahim M, Aravamudhan S, Krüger M et al. Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes. J BIOL CHEM. 2014 Jan 17;289(3):1282-1293. https://doi.org/10.1074/jbc.M113.479030

Bibtex

@article{8930b65e42aa4744a068fdfe45fbc2b7,
title = "Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes",
abstract = "Telethonin (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.",
keywords = "Amino Acid Substitution, Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cells, Cultured, Connectin, Heart Ventricles, Humans, Male, Mice, Microtubules, Muscle Proteins, Mutation, Missense, Myocytes, Cardiac, Phosphorylation, Protein Kinase C, Rats, Rats, Wistar, Sarcomeres",
author = "Candasamy, {Alexandra J} and Haworth, {Robert S} and Friederike Cuello and Michael Ibrahim and Sriram Aravamudhan and Marcus Kr{\"u}ger and Holt, {Mark R} and Terracciano, {Cesare M N} and Manuel Mayr and Mathias Gautel and Metin Avkiran",
year = "2014",
month = jan,
day = "17",
doi = "10.1074/jbc.M113.479030",
language = "English",
volume = "289",
pages = "1282--1293",
journal = "J BIOL CHEM",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "3",

}

RIS

TY - JOUR

T1 - Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes

AU - Candasamy, Alexandra J

AU - Haworth, Robert S

AU - Cuello, Friederike

AU - Ibrahim, Michael

AU - Aravamudhan, Sriram

AU - Krüger, Marcus

AU - Holt, Mark R

AU - Terracciano, Cesare M N

AU - Mayr, Manuel

AU - Gautel, Mathias

AU - Avkiran, Metin

PY - 2014/1/17

Y1 - 2014/1/17

N2 - Telethonin (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.

AB - Telethonin (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.

KW - Amino Acid Substitution

KW - Animals

KW - Calcium

KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2

KW - Cells, Cultured

KW - Connectin

KW - Heart Ventricles

KW - Humans

KW - Male

KW - Mice

KW - Microtubules

KW - Muscle Proteins

KW - Mutation, Missense

KW - Myocytes, Cardiac

KW - Phosphorylation

KW - Protein Kinase C

KW - Rats

KW - Rats, Wistar

KW - Sarcomeres

U2 - 10.1074/jbc.M113.479030

DO - 10.1074/jbc.M113.479030

M3 - SCORING: Journal article

C2 - 24280220

VL - 289

SP - 1282

EP - 1293

JO - J BIOL CHEM

JF - J BIOL CHEM

SN - 0021-9258

IS - 3

ER -