Group:MUZIC:Telethonin
From Proteopedia
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= Telethonin = | = Telethonin = | ||
| - | + | <StructureSection load='1ya5' size='300' side='left' caption='Telethonin crystal structure by Zou et al. (2006) interacting with Z1 and Z2 Titin domains(PDB entry [[1ya5]])' scene='User:Marcia_Ivonne_Pena_Paz/workbench/Telethonin/Telethonin1/2'> | |
| + | Also known as T-Cap or Titin Cap protein. | ||
== Introduction == | == Introduction == | ||
Revision as of 14:19, 25 October 2012
Telethonin
Also known as T-Cap or Titin Cap protein.
IntroductionTelethonin is a small protein composed of 167 amino acids with a molecular weight of 19KDa; its expression is predominantly specific to striated muscle belonging to the structural machinery of the sarcomere and locating to the Z-disk. Telethonin acts as multifunctional protein linking Titin and other proteins implicated in sarcomere structure and signalling pathways. It is encoded by the Tcap gene in mice (Mus musculus), and TCAP in humans (Homo sapiens), no known homologues have been reported for this gene. In mice it is located in chromosome 11, in humans in the long arm of chromosome 17. Tcap is encoded by two exons, and has non-conserved intragenic sequences. The gene is flanked by two other genes, namely Stard3 upstream separated by 2,8kb, and Pnmt1 downstream separated by 1,7kb. It has three conserved E-box elements at -103bp (E1), -272bp (E2), and -2067bp (E3). For the full activation of the gene the regulation of E1 is highly important. MyoD plays an important role in this regulation all through development, while myogenin mainly during late differentiation into myoblasts. [1]
Tcap is one of the most abundant transcripts in skeletal muscle [2] and it does not have different levels of expression in different types of fibers in skeletal muscle; levels of expression of Tcap are lower in neonatal compared to adult striated muscle. The transcript is accumulated in a linear pattern similar to that of the myosin heavy chain [3]. In these same studies it was reported that denervation leads to decrease in the expression of Tcap transcript, suggesting that locomotor activity is a potential regulator of its maintenance.
Sequence AnnotationTelethonin is comprised of 167 amino acids, the sequence of human, mouse, bovine, porcine Telethonin is available from Uniprot.
StructureTelethonin accumulation is restricted to striated muscle, being found mostly in skeletal and cardiac muscle. It is one of the major components of the sarcomere and localizes to the Z-disc. It was also reported to localize to the nucleus.[4], [5] Studies on Telethonin structure by Zou et al. [6] report that it is made up of (N-terminal in blue and C-ter in orange). This structure is only found in the presence of Titin, Telethonin might adopt a different fold in its absence. The structure of Telethonin was determined using X-ray crystallography. [7],[6] The shape and architecture of the complex of Titin/Telethonin was studied by small-angle- X-ray scattering (SAXS) and then compared to the crystallographic models. [8] This symmetry of Telethonin permits its interaction with Titin. Both are assembled in an antiparallel (Titin:Telethonin). Titin N-terminal domains Z1 and Z2 (two Ig like repeats) interact with the C-terminal region of Telethonin (residues 1-53). Telethonin mediates in the antiparallel assembly of the two Z1Z2 domains.
Function and InteractionsIn early differentiating myocytes Titin C-terminal and Telethonin co-localize so that Titin kinase is close to Telethonin C-terminal, then it can be phosphorylated. This phosphorylation is involved in the reorganization of the cytoskeleton during myofibrillogenesis. [9] This co-localization is not seen in adult myofibrils where it is seen that Titin kinase is localized in the M-band [9]; It was also reported that Telethonin interacts with other proteins including Potassium channel β-subunit of the slow activating component of the delayed rectifier potassium current (IKs) channel (minK) [10], Ankyrin1 [11], and Z-disc proteins FATZ,/Myozenin-1/ Calsarcin-3 [12], and Ankrd2.[13] Telethonin interacts with minK’s cytoplasmic domain, and minK binds specifically to the sixteen C-terminal residues of Telethonin. This suggests that minK, Telethonin and Titin form a complex that links myofibrils to the sarcolemma. This process can be negatively regulated by the phosphorylation of Telethonin on Ser157. This interaction has been shown to occur in cardiac myofibrils, but it has not been reported to exist in skeletal muscle where minK is not expressed. [10]. Telethonin interacts with the N-terminus of FATZ/Myozenin-1/Calsarcin-3 between residues 78-125. This interaction may play a role in mechanosensation and stretch-associated signalling. [12] As part of the mechanical stress/ stretch sensor machinery, Telethonin intreacts with Ankrd2, to transmit the signal to the nucleus so Ankrd2 can regulate gene expression. [13] Telethonin is also involved in signalling processes that regulate muscle development. A feed back loop is formed with Myogenic Regulatory Factors (MyoD, myogenin, Myf5), Telethonin and Myostatin. MyoD possitively regulate Telethonin then Telethonin inhibits Myostatin by interacting with it. MyoD expression is repressed through the Myostatin-Smad3 pathway so when Myostatin is inhibited by Telethonin the repression on MyoD expression is lost. [14] [15] Telethonin is inhibited by MDM2 in a dose dependent manner, MDM2 N-terminus interacts with Telethonin and redirects it to the nucleus. In cells MDM2 is involved in the regulation of proteasomal turnover of Telethonin. [5] Another interaction that has been reported, and also associated with pathology, is the one with bone morphogenetic protein-10 (BMP10). The interaction of Telethonin with BMP10 is described as a sensor of increased wall stress of the left ventricle. A BMP10 variant is associated with hypertension dilated cardiomyopathy; its binding to Telethonin is reduced, and its extracellular secretion is increased, causing cardiomyocyte hypertrophy. [16] Yeast two hybrid screens of skeletal muscle cDNA libraries with baits for the E3 ubiquitin ligases MURF1 and MURF2 have shown an interaction with Telethonin, so there is a MURF1/2 might be targeting Telethonin. [17] It was also shown by Y2H an interaction of the proapototic protein Siva and Telethonin, it was verified by in vitro pull-down assays, and immunoflurescence experiments showed a colocalization of both proteins in transfected HEK293 cells, but not in vivo. [18] Protein Kinase D (PKD) catalytic domain interacts with Telethonin. It was shown that Telethonin has a PKD recognition motif Arg-X-X-Ser, PKD might regulate sarcomeric assembly and turnover through phosphorylation of Telethonin. [19]
Pathologies associated with TelethoninDifferent mutations in Telethonin have been associated with several myopathies. Mutations can lead to limb-girdle muscular dystrophy type 2G (LGMD2G) [20], to hypertrophic cardiopathy, [21] and dilated cardiomyopathy. Two mutations found in the Tcap gene cause a deletion of the Telethonin C-terminal region, losing the site which can be phosphorylated, for example by Titin kinase [20], leading to disruption of the sarcomeric structure; as was observed in a few brazilian families with LGMD2G. Defects in the MLP-Tcap association are linked to human dilated cardiomyopathy and heart failure (Knöll 2002). Mutations that affect ability of MLP to interact with Telethonin result in the loss of Telethonin binding, facilitating its mislocalization from the complex with Titin, leading to defects in the Z-disc and progression of dilated cardiomyopathy. Knöll et al. conclude that genetic mutations causing a incorrect interaction of Telethonin with MLP can lead to a development of human dilated cardiomyopathy through modifications in the conformation and function of Titin. [21] It was reported that in 10 cases of neurogenic atrophy there was a decreased staining for Telethonin in type II fibers, and in early stages of fiber atrophy, [22] indicating a selective downregulation of Telethonin. These observations can be related to in vivo studies done in rats, in which after short term denervation (two days), Tcap transcript is reduced by about 50% in skeletal muscle. [3]. References
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