Group:MUZIC:Telethonin
From Proteopedia
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| - | It is encoded by the ''Tcap'' gene, in mice (''Mus musculus'') and | + | It is encoded by the ''Tcap'' gene, in mice (''Mus musculus'') and ''TCAP'' in humans (''Homo sapiens''). |
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). | 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. <ref>PMID:21305318</ref> | 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. <ref>PMID:21305318</ref> | ||
| - | [[Image: Tcap regulation2.jpg]] | + | [[Image:Tcap regulation2.jpg]] |
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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. | ||
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| + | == ''Tcap'' gene product, the protein Telethonin == | ||
| - | 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 name="1">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. | ||
| - | == “Tcap” gene product, the protein Telethonin == | ||
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>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 <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>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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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> | 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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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>, | 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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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> | 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> | ||
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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> | 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> | ||
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== Pathologies associated with telethonin == | == Pathologies associated with telethonin == | ||
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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., <ref>PMID: 12507422</ref>, and dilated cardiomyopathy. | 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., <ref>PMID: 12507422</ref>, and dilated cardiomyopathy. | ||
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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. | 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. | ||
| - | 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 | + | 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>. |
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<scene name='User:Marcia_Ivonne_Pena_Paz/workbench/Telethonin/Telethonin_red/2'>Telethonin</scene> | <scene name='User:Marcia_Ivonne_Pena_Paz/workbench/Telethonin/Telethonin_red/2'>Telethonin</scene> | ||
Revision as of 11:58, 18 August 2011
Telethonin
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