Telethonin is a 19.0 kDa protein composed of 167 amino acids.[8]
Telethonin has a unique β-sheet structure, which enables antiparallel association with the
Titin Z1-Z2 domains in
cardiac and
skeletal muscle.[9] Structural analysis of full-length Telethonin with the
N-terminal region of
Titin indicate that the
C-terminus of Telethonin is critical for the dimerization of two Telethonin/
Titin complexes into a higher oligomeric structure.[10]
Function
Telethonin expression is developmentally regulated in both
cardiac and
skeletal muscle and is thought to be critical to sarcomere assembly.[11] Telethonin was found to be a late assembling protein only present in mature
myofibrils at
Z-discs.[12]
Telethonin forms a complex with
muscle LIM protein (MLP) at
sarcomere Z-discs, which constitutes part of the
cardiomyocyte stretch sensory mechanism.[13] 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
T-tubule membranes surrounding
Z-lines in the inner
myocardium.[14] In addition, Telethonin interacts with the sodium channel
Na(v)1.5, and alters the activation kinetics via doubling the window current.[15] These data suggest that Telethonin may constitute a mechano-electrical links between
Z-lines and
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
T-tubule structure and function, as well as apoptosis in the heart. Telethonin KO animals showed preserved
Titin anchoring at baseline, and instead showed a profound deficit during
nuclear biomechanical stress in modulating the turnover of the proapoptotic
p53 protein.[16] Telethonin KO animals also displayed
calcium transient dysynchrony,
T-tubule loss and depressed
L-type calcium channel function.[17]
The intracellular degradation of Telethonin is regulated by
MDM2 in a
proteasomal-dependent yet
ubiquitin-independent manner.[21] Telethonin specifically interacts with the pro-apoptotic protein
Siva, suggesting that Telethonin may be involved in the mechanism underlying
Coxsackievirus B3 infection in acute and chronic
myocarditis[22]
Telethonin was also identified to be targeted and regulated by transcriptional activators
CLOCK and
BMAL1, thus demonstrating that TCAP is a circadian regulated gene.[23]
Two mutations in Telethonin,
Thr137
Ile and
Arg153
His have been associated with
hypertrophic cardiomyopathy, which enhance the binding of Telethonin with
Titin and
MYOZ2. The
Glu132
Gln mutation has been associated with
dilated cardiomyopathy, which has the opposite effect in that it impairs the binding of Telethonin with
Titin and
MYOZ2.[31] Mutations in
Titin associated with
dilated cardiomyopathy, including
Val54
Met, have been shown specifically to impair binding of
Titin with Telethonin.[32] In a mouse model of
dilated cardiomyopathy, recapitulating the human
dilated cardiomyopathy mutation in
MLP,
Trp4
Arg, studies have found that this mutation disrupts normal binding and localization of
MLP with Telethonin.[13] In a rat model of hypertension-induced
cardiomyopathy, a human variant of
BMP10,
Thr326
Ile, showed decreased binding to Telethonin and increased extracellular secretion.[33]
^Pinotsis N, Petoukhov M, Lange S, Svergun D, Zou P, Gautel M, Wilmanns M (Aug 2006). "Evidence for a dimeric assembly of two titin/telethonin complexes induced by the telethonin C-terminus". Journal of Structural Biology. 155 (2): 239–50.
doi:
10.1016/j.jsb.2006.03.028.
PMID16713295.
^Mason P, Bayol S, Loughna PT (Apr 1999). "The novel sarcomeric protein telethonin exhibits developmental and functional regulation". Biochemical and Biophysical Research Communications. 257 (3): 699–703.
doi:
10.1006/bbrc.1999.0531.
PMID10208846.
^
abFurukawa T, Ono Y, Tsuchiya H, Katayama Y, Bang ML, Labeit D, Labeit S, Inagaki N, Gregorio CC (Nov 2001). "Specific interaction of the potassium channel beta-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system". Journal of Molecular Biology. 313 (4): 775–84.
doi:
10.1006/jmbi.2001.5053.
PMID11697903.
^
abMayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M (Oct 1998). "Structural basis for activation of the titin kinase domain during myofibrillogenesis". Nature. 395 (6705): 863–9.
Bibcode:
1998Natur.395..863M.
doi:
10.1038/27603.
PMID9804419.
S2CID4426977.
^Tian LF, Li HY, Jin BF, Pan X, Man JH, Zhang PJ, Li WH, Liang B, Liu H, Zhao J, Gong WL, Zhou T, Zhang XM (Jun 2006). "MDM2 interacts with and downregulates a sarcomeric protein, TCAP". Biochemical and Biophysical Research Communications. 345 (1): 355–61.
doi:
10.1016/j.bbrc.2006.04.108.
PMID16678796..
^Andersen PS, Havndrup O, Hougs L, Sørensen KM, Jensen M, Larsen LA, Hedley P, Thomsen AR, Moolman-Smook J, Christiansen M, Bundgaard H (Mar 2009). "Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives". Human Mutation. 30 (3): 363–70.
doi:
10.1002/humu.20862.
PMID19035361.
S2CID30898294.
^Itoh-Satoh M, Hayashi T, Nishi H, Koga Y, Arimura T, Koyanagi T, Takahashi M, Hohda S, Ueda K, Nouchi T, Hiroe M, Marumo F, Imaizumi T, Yasunami M, Kimura A (Feb 2002). "Titin mutations as the molecular basis for dilated cardiomyopathy". Biochemical and Biophysical Research Communications. 291 (2): 385–93.
doi:
10.1006/bbrc.2002.6448.
PMID11846417.
S2CID1824336.
^Nakano N, Hori H, Abe M, Shibata H, Arimura T, Sasaoka T, Sawabe M, Chida K, Arai T, Nakahara K, Kubo T, Sugimoto K, Katsuya T, Ogihara T, Doi Y, Izumi T, Kimura A (Dec 2007). "Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy". American Journal of Physiology. Heart and Circulatory Physiology. 293 (6): H3396–403.
doi:
10.1152/ajpheart.00311.2007.
PMID17921333.
S2CID45084505.
^Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G (May 2004). "The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle". Journal of Molecular Biology. 339 (2): 313–25.
doi:
10.1016/j.jmb.2004.03.071.
PMID15136035.
^Nakano N, Hori H, Abe M, Shibata H, Arimura T, Sasaoka T, Sawabe M, Chida K, Arai T, Nakahara K, Kubo T, Sugimoto K, Katsuya T, Ogihara T, Doi Y, Izumi T, Kimura A (Dec 2007). "Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy". American Journal of Physiology. Heart and Circulatory Physiology. 293 (6): H3396–403.
doi:
10.1152/ajpheart.00311.2007.
PMID17921333.
S2CID45084505.
^Tian LF, Li HY, Jin BF, Pan X, Man JH, Zhang PJ, Li WH, Liang B, Liu H, Zhao J, Gong WL, Zhou T, Zhang XM (Jun 2006). "MDM2 interacts with and downregulates a sarcomeric protein, TCAP". Biochemical and Biophysical Research Communications. 345 (1): 355–61.
doi:
10.1016/j.bbrc.2006.04.108.
PMID16678796.
Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M (Oct 1998). "Structural basis for activation of the titin kinase domain during myofibrillogenesis". Nature. 395 (6705): 863–9.
Bibcode:
1998Natur.395..863M.
doi:
10.1038/27603.
PMID9804419.
S2CID4426977.
Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT, Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne DE (Feb 2000). "Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin". Nature Genetics. 24 (2): 163–6.
doi:
10.1038/72822.
PMID10655062.
S2CID8698402.
Schröder R, Reimann J, Iakovenko A, Mues A, Bönnemann CG, Matten J, Gautel M (2002). "Early and selective disappearance of telethonin protein from the sarcomere in neurogenic atrophy". Journal of Muscle Research and Cell Motility. 22 (3): 259–64.
doi:
10.1023/A:1012242011109.
PMID11763198.
S2CID22553971.
Katoh M, Katoh M (Apr 2004). "Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon". International Journal of Oncology. 24 (4): 757–63.
doi:
10.3892/ijo.24.4.757.
PMID15010812.
Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G (May 2004). "The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle". Journal of Molecular Biology. 339 (2): 313–25.
doi:
10.1016/j.jmb.2004.03.071.
PMID15136035.
Telethonin is a 19.0 kDa protein composed of 167 amino acids.[8]
Telethonin has a unique β-sheet structure, which enables antiparallel association with the
Titin Z1-Z2 domains in
cardiac and
skeletal muscle.[9] Structural analysis of full-length Telethonin with the
N-terminal region of
Titin indicate that the
C-terminus of Telethonin is critical for the dimerization of two Telethonin/
Titin complexes into a higher oligomeric structure.[10]
Function
Telethonin expression is developmentally regulated in both
cardiac and
skeletal muscle and is thought to be critical to sarcomere assembly.[11] Telethonin was found to be a late assembling protein only present in mature
myofibrils at
Z-discs.[12]
Telethonin forms a complex with
muscle LIM protein (MLP) at
sarcomere Z-discs, which constitutes part of the
cardiomyocyte stretch sensory mechanism.[13] 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
T-tubule membranes surrounding
Z-lines in the inner
myocardium.[14] In addition, Telethonin interacts with the sodium channel
Na(v)1.5, and alters the activation kinetics via doubling the window current.[15] These data suggest that Telethonin may constitute a mechano-electrical links between
Z-lines and
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
T-tubule structure and function, as well as apoptosis in the heart. Telethonin KO animals showed preserved
Titin anchoring at baseline, and instead showed a profound deficit during
nuclear biomechanical stress in modulating the turnover of the proapoptotic
p53 protein.[16] Telethonin KO animals also displayed
calcium transient dysynchrony,
T-tubule loss and depressed
L-type calcium channel function.[17]
The intracellular degradation of Telethonin is regulated by
MDM2 in a
proteasomal-dependent yet
ubiquitin-independent manner.[21] Telethonin specifically interacts with the pro-apoptotic protein
Siva, suggesting that Telethonin may be involved in the mechanism underlying
Coxsackievirus B3 infection in acute and chronic
myocarditis[22]
Telethonin was also identified to be targeted and regulated by transcriptional activators
CLOCK and
BMAL1, thus demonstrating that TCAP is a circadian regulated gene.[23]
Two mutations in Telethonin,
Thr137
Ile and
Arg153
His have been associated with
hypertrophic cardiomyopathy, which enhance the binding of Telethonin with
Titin and
MYOZ2. The
Glu132
Gln mutation has been associated with
dilated cardiomyopathy, which has the opposite effect in that it impairs the binding of Telethonin with
Titin and
MYOZ2.[31] Mutations in
Titin associated with
dilated cardiomyopathy, including
Val54
Met, have been shown specifically to impair binding of
Titin with Telethonin.[32] In a mouse model of
dilated cardiomyopathy, recapitulating the human
dilated cardiomyopathy mutation in
MLP,
Trp4
Arg, studies have found that this mutation disrupts normal binding and localization of
MLP with Telethonin.[13] In a rat model of hypertension-induced
cardiomyopathy, a human variant of
BMP10,
Thr326
Ile, showed decreased binding to Telethonin and increased extracellular secretion.[33]
^Pinotsis N, Petoukhov M, Lange S, Svergun D, Zou P, Gautel M, Wilmanns M (Aug 2006). "Evidence for a dimeric assembly of two titin/telethonin complexes induced by the telethonin C-terminus". Journal of Structural Biology. 155 (2): 239–50.
doi:
10.1016/j.jsb.2006.03.028.
PMID16713295.
^Mason P, Bayol S, Loughna PT (Apr 1999). "The novel sarcomeric protein telethonin exhibits developmental and functional regulation". Biochemical and Biophysical Research Communications. 257 (3): 699–703.
doi:
10.1006/bbrc.1999.0531.
PMID10208846.
^
abFurukawa T, Ono Y, Tsuchiya H, Katayama Y, Bang ML, Labeit D, Labeit S, Inagaki N, Gregorio CC (Nov 2001). "Specific interaction of the potassium channel beta-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system". Journal of Molecular Biology. 313 (4): 775–84.
doi:
10.1006/jmbi.2001.5053.
PMID11697903.
^
abMayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M (Oct 1998). "Structural basis for activation of the titin kinase domain during myofibrillogenesis". Nature. 395 (6705): 863–9.
Bibcode:
1998Natur.395..863M.
doi:
10.1038/27603.
PMID9804419.
S2CID4426977.
^Tian LF, Li HY, Jin BF, Pan X, Man JH, Zhang PJ, Li WH, Liang B, Liu H, Zhao J, Gong WL, Zhou T, Zhang XM (Jun 2006). "MDM2 interacts with and downregulates a sarcomeric protein, TCAP". Biochemical and Biophysical Research Communications. 345 (1): 355–61.
doi:
10.1016/j.bbrc.2006.04.108.
PMID16678796..
^Andersen PS, Havndrup O, Hougs L, Sørensen KM, Jensen M, Larsen LA, Hedley P, Thomsen AR, Moolman-Smook J, Christiansen M, Bundgaard H (Mar 2009). "Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives". Human Mutation. 30 (3): 363–70.
doi:
10.1002/humu.20862.
PMID19035361.
S2CID30898294.
^Itoh-Satoh M, Hayashi T, Nishi H, Koga Y, Arimura T, Koyanagi T, Takahashi M, Hohda S, Ueda K, Nouchi T, Hiroe M, Marumo F, Imaizumi T, Yasunami M, Kimura A (Feb 2002). "Titin mutations as the molecular basis for dilated cardiomyopathy". Biochemical and Biophysical Research Communications. 291 (2): 385–93.
doi:
10.1006/bbrc.2002.6448.
PMID11846417.
S2CID1824336.
^Nakano N, Hori H, Abe M, Shibata H, Arimura T, Sasaoka T, Sawabe M, Chida K, Arai T, Nakahara K, Kubo T, Sugimoto K, Katsuya T, Ogihara T, Doi Y, Izumi T, Kimura A (Dec 2007). "Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy". American Journal of Physiology. Heart and Circulatory Physiology. 293 (6): H3396–403.
doi:
10.1152/ajpheart.00311.2007.
PMID17921333.
S2CID45084505.
^Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G (May 2004). "The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle". Journal of Molecular Biology. 339 (2): 313–25.
doi:
10.1016/j.jmb.2004.03.071.
PMID15136035.
^Nakano N, Hori H, Abe M, Shibata H, Arimura T, Sasaoka T, Sawabe M, Chida K, Arai T, Nakahara K, Kubo T, Sugimoto K, Katsuya T, Ogihara T, Doi Y, Izumi T, Kimura A (Dec 2007). "Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy". American Journal of Physiology. Heart and Circulatory Physiology. 293 (6): H3396–403.
doi:
10.1152/ajpheart.00311.2007.
PMID17921333.
S2CID45084505.
^Tian LF, Li HY, Jin BF, Pan X, Man JH, Zhang PJ, Li WH, Liang B, Liu H, Zhao J, Gong WL, Zhou T, Zhang XM (Jun 2006). "MDM2 interacts with and downregulates a sarcomeric protein, TCAP". Biochemical and Biophysical Research Communications. 345 (1): 355–61.
doi:
10.1016/j.bbrc.2006.04.108.
PMID16678796.
Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M (Oct 1998). "Structural basis for activation of the titin kinase domain during myofibrillogenesis". Nature. 395 (6705): 863–9.
Bibcode:
1998Natur.395..863M.
doi:
10.1038/27603.
PMID9804419.
S2CID4426977.
Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT, Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne DE (Feb 2000). "Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin". Nature Genetics. 24 (2): 163–6.
doi:
10.1038/72822.
PMID10655062.
S2CID8698402.
Schröder R, Reimann J, Iakovenko A, Mues A, Bönnemann CG, Matten J, Gautel M (2002). "Early and selective disappearance of telethonin protein from the sarcomere in neurogenic atrophy". Journal of Muscle Research and Cell Motility. 22 (3): 259–64.
doi:
10.1023/A:1012242011109.
PMID11763198.
S2CID22553971.
Katoh M, Katoh M (Apr 2004). "Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon". International Journal of Oncology. 24 (4): 757–63.
doi:
10.3892/ijo.24.4.757.
PMID15010812.
Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G (May 2004). "The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle". Journal of Molecular Biology. 339 (2): 313–25.
doi:
10.1016/j.jmb.2004.03.071.
PMID15136035.