Group:MUZIC:Telethonin

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Also known as T-Cap or Titin Cap protein.
Also known as T-Cap or Titin Cap protein.
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It is a small protein of 19kDa, 167 amino acids. Predominantly expressed in striated muscle. It is a structural protein of the muscle; it is associated to the Z-disc in the sarcomere. It acts as link between titin and other proteins implicated in muscle structure and signalling.
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It is a small protein of 19kDa, 167 amino acids. It is predominantly expressed in striated muscle. It is a structural protein of the muscle; it is associated to the Z-disc in the sarcomere. It acts as multifunctional protein linking titin and other proteins implicated in sarcomere structure and signalling pathways.
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== Gene regulation and expression ==
== Gene regulation and expression ==
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At the transcriptional level it is thought that there is only one isoform of Tcap, and it is one of the most abundant transcripts in skeletal muscle <ref>PMID:9350988</ref>. It does not have different levels of expression in different types of 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 <ref>PMID: 10208846</ref>. In these same studies it was reported that denervation leads to decrease in the expression of Tcap, suggesting that locomotor activity is a potential regulator of its maintenance.
At the transcriptional level it is thought that there is only one isoform of Tcap, and it is one of the most abundant transcripts in skeletal muscle <ref>PMID:9350988</ref>. It does not have different levels of expression in different types of 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 <ref>PMID: 10208846</ref>. In these same studies it was reported that denervation leads to decrease in the expression of Tcap, suggesting that locomotor activity is a potential regulator of its maintenance.
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== Tcap protein ==
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== “Tcap” gene product, the protein Telethonin ==
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Telethonin protein is found mostly in skeletal and cardiac muscle. It is one of the major components of the sarcomere, it is localized to the Z-disc.
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Telethonin protein is found mostly in skeletal and cardiac muscle. It is one of the major components of the sarcomere, it is localized to the Z-disc. It was also reported a nuclear localization.<ref>PMID:12379311 </ref> <ref>PMID:16678796 </ref>
Studies on telethonin structure by Zou et al. <ref>PMID:16407954</ref> report that it is made up of five stranded antiparallel β-sheets extended by two wing-shaped β-hairpin motifs (A-B, C-D). These two motifs are related by an approximate two-fold symmetry, which generates an almost perfect palindromic arrangement.
Studies on telethonin structure by Zou et al. <ref>PMID:16407954</ref> report that it is made up of five stranded antiparallel β-sheets extended by two wing-shaped β-hairpin motifs (A-B, C-D). These two motifs are related by an approximate two-fold symmetry, which generates an almost perfect palindromic arrangement.
The structure of telethonin was determined using X-ray crystallography <ref>PMID:12446666</ref>,<ref>PMID:16407954</ref> . 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. They also used in-vitro experiments to follow the formation of the complex in non-myogenic Cos1 cells, in order to understand if the assemblage is possible <ref>PMID:16713295</ref>
The structure of telethonin was determined using X-ray crystallography <ref>PMID:12446666</ref>,<ref>PMID:16407954</ref> . 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. They also used in-vitro experiments to follow the formation of the complex in non-myogenic Cos1 cells, in order to understand if the assemblage is possible <ref>PMID:16713295</ref>
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This symmetry of telethonin permits its interaction with titin. Both are assembled in an antiparallel <scene name='User:Marcia_Ivonne_Pena_Paz/workbench/Telethonin/Telethonin-titin/1'>sandwich 2:1</scene> (titin:telethonin). Titin N-terminal domains Z1 and Z2 interact with the N-terminal region of telethonin (residues 1-53). Telethonin mediates in the antiparallel assembly of the two Z1Z2domains.
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This symmetry of telethonin permits its interaction with titin. Both are assembled in an antiparallel <scene name='User:Marcia_Ivonne_Pena_Paz/workbench/Telethonin/Telethonin-titin/1'>sandwich 2:1</scene> (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 Z1Z2domains.
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In early differentiating myocytes titin C-terminal and telethonin co-localize and titin kinase is close to telethonin C-terminal, and it is phosphorylated. This phosphorylation is involved in the reorganization of the cytoskeleton during myofibrillogenesis. <ref>PMID: 9804419 </ref> This co-localization is not seen in adult myofibrils, titin kinase is reported to localize in the M-band <ref>PMID: 9804419</ref>; It was also informed 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) <ref>PMID: 11697903</ref>, ankyrin1, and Z-disc proteins FATZ,/Myozenin-1/ Calsarcin-3 <ref>PMID: 11842093</ref>, and Ankrd2.<ref>PMID:15136035</ref>
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In early differentiating myocytes titin C-terminal and telethonin co-localize and titin kinase is close to telethonin C-terminal, and it is phosphorylated. This phosphorylation is involved in the reorganization of the cytoskeleton during myofibrillogenesis. <ref>PMID: 9804419 </ref> This co-localization is not seen in adult myofibrils, titin kinase is reported to localize in the M-band <ref>PMID: 9804419</ref>; It was also informed that telethonin interacts with other proteins including: Potassium channel subunit minK/isk <ref>PMID: 11697903</ref>, ankyrin1, and Z-disc proteins FATZ, Calsarcin-3 <ref>PMID: 11842093</ref>, Ankrd2,<ref>PMID:15136035</ref> and MLP. <ref>PMID: 12507422</ref>
 
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[[Image:TelethoninandID.jpg]]
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Telethonin interacts with minK’s cytoplasmic domain. MinK binds specifically to the sixteen C-terminal residues of telethonin. This suggest a that minK, telethonin ant titin form a complex that links myofibrils to the sarcolemma. Phosphorilation of telethonin in Ser157 is a negative regulation for this interaction. This interaction occurs in cardiac myofibrils, it has been reported that minK is not expressed in skeletal muscle.<ref>PMID: 11697903</ref>,
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MLP-Telethonin complex is part of the mechanical stretch sensor machinery in cardiac muscle. The binding site of telethonin and MLP is adjacent to the titing binding domain. This interaction is critical for maintaining normal cardiac function. MLP is required for the stabilization of telethonin-titin complex, this mechanism is not clear yet.
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Telethonin interacts with FATZ/Myozenin-1/Calsarcin-3 N-terminal between residues 78-125. It might be an association as mechanosensing and stretch-associated signalling machinery. <ref>PMID: 11842093</ref>
The interaction between Ankrd2 and telethonin has been proposed as a sensor of muscle stress/stretch and a starting point for the transmission of the mechanical signal to the nucleus regulating gene expression. <ref>PMID: 15136035</ref>
The interaction between Ankrd2 and telethonin has been proposed as a sensor of muscle stress/stretch and a starting point for the transmission of the mechanical signal to the nucleus regulating gene expression. <ref>PMID: 15136035</ref>
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Telethonin is also involved in signalling processes that regulate muscle development. A feed back loop is formed with MRFs (MyoD, myogenin, Myf5) regulating Tcap gene expression; telethonin interacts with myostatin, inhibiting it. So it regulates MyoD through the Myostatin – Smad3 pathway. <ref>PMID:18440815</ref>.
Telethonin is also involved in signalling processes that regulate muscle development. A feed back loop is formed with MRFs (MyoD, myogenin, Myf5) regulating Tcap gene expression; telethonin interacts with myostatin, inhibiting it. So it regulates MyoD through the Myostatin – Smad3 pathway. <ref>PMID:18440815</ref>.
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[[Image:Telethonin Myostatin.jpg]]
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There is an interaction with MDM2 N-terminal. MDM2 is capable of redirecting telethonin to the nucleus. Telethonin is inhibited by MDM2 in a dose dependent manner. In cells MDM2 is involved in the regulation of proteasomal turnover of telethonin. <ref>PMID:16678796 </ref>
== Pathologies associated with telethonin ==
== Pathologies associated with telethonin ==

Revision as of 09:11, 16 August 2011

Telethonin

Telethonin crystal structure by Zou et al. (2006) interacting with Z1 and Z2 titin domains(PDB entry 1ya5)

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Proteopedia Page Contributors and Editors (what is this?)

Marcia Ivonne Peña Paz, Nikos Pinotsis, Jaime Prilusky

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