Telethonin

Telethonin, also known as Tcap, is a is_associated_with::protein that in humans is encoded by the TCAP is_associated_with::gene. Telethonin is expressed in cardiac and is_associated_with::skeletal muscle at Z-discs and functions to regulate sarcomere assembly, is_associated_with::T-tubule function and is_associated_with::apoptosis. Telethonin has been implicated in several diseases, including is_associated_with::limb-girdle muscular dystrophy, is_associated_with::hypertrophic cardiomyopathy, is_associated_with::dilated cardiomyopathy and idiopathic is_associated_with::cardiomyopathy.

Structure
Telethonin is a 19.0 kDa protein composed of 167 amino acids. Telethonin has a unique β-sheet structure, which enables antiparallel association with the is_associated_with::Titin Z1-Z2 domains in cardiac and is_associated_with::skeletal muscle. Structural analysis of full-length Telethonin with the N-terminal region of is_associated_with::Titin indicate that the is_associated_with::C-terminus of Telethonin is critical for the dimerization of two Telethonin/is_associated_with::Titin complexes into a higher oligomeric structure.

Function
Telethonin expression is developmentally regulated in both cardiac and is_associated_with::skeletal muscle and is thought to be critical to sarcomere assembly. Telethonin was found to be a late assembling protein only present in mature is_associated_with::myofibrils at Z-discs.

Telethonin forms a complex with MLP at Z-discs, which constitutes part of the is_associated_with::cardiomyocyte stretch sensory mechanism. It has also been shown that Telethonin binds to the beta-subunit of the slow activating component of the delayed rectifier potassium channel, MinK, in areas localized to is_associated_with::T-tubule membranes surrounding Z-lines in the inner is_associated_with::myocardium. In addition, Telethonin interacts with the sodium channel Na(v)1.5, and alters the activation kinetics via doubling the window current. These data suggest that Telethonin may constitute a mechano-electrical links between Z-lines and is_associated_with::T-tubules. Further functional evidence for this has come from studies utilizing a Telethonin-knockout mouse (KO), which have shown that Telethonin is involved in is_associated_with::T-tubule structure and function, as well as apoptosis in the heart. Telethonin KO animals showed preserved is_associated_with::Titin anchoring at baseline, and instead showed a profound deficit during nuclear biomechanical stress in modulating the turnover of the proapoptotic is_associated_with::p53 protein. Telethonin KO animals also displayed is_associated_with::calcium transient dysynchrony, is_associated_with::T-tubule loss and depressed is_associated_with::L-type calcium channel function.

Telethonin is a substrate of titin kinase, protein kinase D (PKD) and CaM Kinase II. Telethonin, as well as is_associated_with::TNNI3, MYBPC3 and is_associated_with::MYOM2 are phosphorylated by PKD in is_associated_with::cardiomyocytes, and this leads to a reduction in calcium sensitivity of is_associated_with::myofilaments, as well as accelerated is_associated_with::crossbridge kinetics. Bis-phosphorylation of Telethonin specifically at sites is_associated_with::Serine-157 and is_associated_with::Serine-161 has been shown to be essential for normal is_associated_with::T-tubule organization and intracellular is_associated_with::calcium transient kinetics.

The intracellular degradation of Telethonin is regulated by is_associated_with::MDM2 in a proteasomal-dependent yet is_associated_with::ubiquitin-independent manner. Telethonin specifically interacts with the pro-apoptotic protein Siva, suggesting that Telethonin may be involved in the mechanism underlying is_associated_with::Coxsackievirus B3 infection in acute and chronic is_associated_with::myocarditis

Telethonin was also identified to be targeted and regulated by transcriptional activators is_associated_with::CLOCK and is_associated_with::BMAL1, thus demonstrating that TCAP is a circadian regulated gene.

Clinical Significance
Mutations in this gene are associated with is_associated_with::limb-girdle muscular dystrophy type 2G, is_associated_with::hypertrophic cardiomyopathy,  is_associated_with::dilated cardiomyopathy,  idiopathic is_associated_with::cardiomyopathy, and gastrointestinal smooth muscle-related diseases.

Two mutations in Telethonin, Thr137Ile and Arg153His have been associated with is_associated_with::hypertrophic cardiomyopathy, which enhance the binding of Telethonin with is_associated_with::Titin and is_associated_with::MYOZ2. The Glu132Gln mutation has been associated with is_associated_with::dilated cardiomyopathy, which has the opposite effect in that it impairs the binding of Telethonin with is_associated_with::Titin and is_associated_with::MYOZ2. Mutations in is_associated_with::Titin associated with is_associated_with::dilated cardiomyopathy, including Val54Met, have been shown specifically to impair binding of is_associated_with::Titin with Telethonin. In a mouse model of is_associated_with::dilated cardiomyopathy, recapitulating the human is_associated_with::dilated cardiomyopathy mutation in MLP, Trp4Arg, studies have found that this mutation disrupts normal binding and localization of MLP with Telethonin. In a rat model of hypertension-induced is_associated_with::cardiomyopathy, a human variant of is_associated_with::BMP10, Thr326Ile, showed decreased binding to Telethonin and increased extracellular secretion.

Interactions
Telethonin has been shown to interact with:


 * is_associated_with::ANKRD2,
 * is_associated_with::BMP10,
 * MLP,
 * MinK,
 * is_associated_with::MDM2,
 * is_associated_with::MSTN,
 * is_associated_with::MYOZ1,
 * is_associated_with::MYOZ2,
 * is_associated_with::PRKD1,
 * is_associated_with::SCN5A,
 * SIVA, and
 * is_associated_with::Titin,