Group:MUZIC:Telethonin
From Proteopedia
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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> | + | 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 name="a"> PMID:16678796 </ref> |
| - | Studies on telethonin structure by Zou et al. <ref>PMID:16407954</ref> report that it is made up of <scene name='User:Marcia_Ivonne_Pena_Paz/workbench/Telethonin/Telethonin_nter_cter/1'>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.</scene> (N-terminal in blue and C-ter in orange) | + | Studies on telethonin structure by Zou et al. <ref name="b"> PMID:16407954 </ref> report that it is made up of <scene name='User:Marcia_Ivonne_Pena_Paz/workbench/Telethonin/Telethonin_nter_cter/1'>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.</scene> (N-terminal in blue and C-ter in orange) |
| - | The structure of telethonin was determined using X-ray crystallography. <ref>PMID:12446666</ref>,<ref name=" | + | The structure of telethonin was determined using X-ray crystallography. <ref>PMID:12446666</ref>,<ref name="b" /> 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> |
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. | 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. | ||
| - | 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 | + | 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 name="c"> PMID:9804419 </ref> This co-localization is not seen in adult myofibrils, titin kinase is reported to localize in the M-band <ref name="c" />; 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 name="d"> PMID:11697903 </ref>, ankyrin1, and Z-disc proteins FATZ,/Myozenin-1/ Calsarcin-3 <ref name="e"> PMID:11842093 </ref>, and Ankrd2.<ref name="f"> PMID:15136035 </ref> |
| - | 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 | + | 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 name="d" /> |
| - | 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 | + | 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 name="e" /> |
| - | 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 | + | 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 name="f" /> |
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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| - | Different mutations in telethonin have been associated with several myopathies. Mutations can lead to limb-girdle muscular dystrophy type 2G (LGMD2G) <ref>PMID: 10655062 </ref>, to hypertrophic cardiopathy | + | Different mutations in telethonin have been associated with several myopathies. Mutations can lead to limb-girdle muscular dystrophy type 2G (LGMD2G) <ref name="g"> PMID:10655062 </ref>, to hypertrophic cardiopathy, <ref name="h"> PMID:12507422 </ref> 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 <ref | + | 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 <ref name="g" />, 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. <ref | + | 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. <ref name="h" /> |
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, <ref>PMID: 11763198</ref> 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. <ref>PMID:10208846</ref>. | 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, <ref>PMID: 11763198</ref> 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. <ref>PMID:10208846</ref>. | ||
Revision as of 11:59, 22 August 2011
Telethonin
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