Telethonin is a 19.0 kDa protein composed of 167 amino acids.[4]
Telethonin has a unique β-sheet structure, which enables antiparallel association with the Titin Z1-Z2 domains in cardiac and skeletal muscle.[5] 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.[6]
Function
Telethonin expression is developmentally regulated in both cardiac and skeletal muscle and is thought to be critical to sarcomere assembly.[7] Telethonin was found to be a late assembling protein only present in mature myofibrils at Z-discs.[8]
Telethonin forms a complex with MLP at Z-discs, which constitutes part of the cardiomyocyte stretch sensory mechanism.[9] 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.[10] In addition, Telethonin interacts with the sodium channel Na(v)1.5, and alters the activation kinetics via doubling the window current.[11] 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.[12] Telethonin KO animals also displayed calcium transient dysynchrony, T-tubule loss and depressed L-type calcium channel function.[13]
The intracellular degradation of Telethonin is regulated by MDM2 in a proteasomal-dependent yet ubiquitin-independent manner.[17] 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[18]
Telethonin was also identified to be targeted and regulated by transcriptional activators CLOCK and BMAL1, thus demonstrating that TCAP is a circadian regulated gene.[19]
Two mutations in Telethonin, Thr137Ile and Arg153His have been associated with hypertrophic cardiomyopathy, which enhance the binding of Telethonin with Titin and MYOZ2. The Glu132Gln mutation has been associated with dilated cardiomyopathy, which has the opposite effect in that it impairs the binding of Telethonin with Titin and MYOZ2.[27] Mutations in Titin associated with dilated cardiomyopathy, including Val54Met, have been shown specifically to impair binding of Titin with Telethonin.[28] In a mouse model of dilated cardiomyopathy, recapitulating the human dilated cardiomyopathy mutation in MLP, Trp4Arg, studies have found that this mutation disrupts normal binding and localization of MLP with Telethonin.[9] In a rat model of hypertension-induced cardiomyopathy, a human variant of BMP10, Thr326Ile, showed decreased binding to Telethonin and increased extracellular secretion.[29]
↑Valle G, Faulkner G, De Antoni A, Pacchioni B, Pallavicini A, Pandolfo D, Tiso N, Toppo S, Trevisan S, Lanfranchi G (Sep 1997). "Telethonin, a novel sarcomeric protein of heart and skeletal muscle". FEBS Letters. 415 (2): 163–8. doi:10.1016/S0014-5793(97)01108-3. PMID9350988.
↑Zou P, Pinotsis N, Lange S, Song YH, Popov A, Mavridis I, Mayans OM, Gautel M, Wilmanns M (Jan 2006). "Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk". Nature. 439 (7073): 229–33. doi:10.1038/nature04343. PMID16407954.
↑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.
↑ 9.09.19.2Knöll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR (Dec 2002). "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy". Cell. 111 (7): 943–55. doi:10.1016/s0092-8674(02)01226-6. PMID12507422.
↑ 10.010.1Furukawa 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.
↑ 14.014.1Mayans 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. doi:10.1038/27603. PMID9804419.
↑Haworth RS, Cuello F, Herron TJ, Franzen G, Kentish JC, Gautel M, Avkiran M (Nov 2004). "Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function". Circulation Research. 95 (11): 1091–9. doi:10.1161/01.RES.0000149299.34793.3c. PMID15514163.
↑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..
↑Mihatsch K, Nestler M, Saluz HP, Henke A, Munder T (Jan 2009). "Proapoptotic protein Siva binds to the muscle protein telethonin in cardiomyocytes during coxsackieviral infection". Cardiovascular Research. 81 (1): 108–15. doi:10.1093/cvr/cvn276. PMID18849585.
↑Vainzof M, Moreira ES, Suzuki OT, Faulkner G, Valle G, Beggs AH, Carpen O, Ribeiro AF, Zanoteli E, Gurgel-Gianneti J, Tsanaclis AM, Silva HC, Passos-Bueno MR, Zatz M (Oct 2002). "Telethonin protein expression in neuromuscular disorders". Biochimica et Biophysica Acta. 1588 (1): 33–40. doi:10.1016/s0925-4439(02)00113-8. PMID12379311.
↑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.
↑Hirtle-Lewis M, Desbiens K, Ruel I, Rudzicz N, Genest J, Engert JC, Giannetti N (Oct 2013). "The genetics of dilated cardiomyopathy: a prioritized candidate gene study of LMNA, TNNT2, TCAP, and PLN". Clinical Cardiology. 36 (10): 628–33. doi:10.1002/clc.22193. PMID24037902.
↑Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knöll R, Hoshijima M, Chien KR, Kimura A (Dec 2004). "Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy". Journal of the American College of Cardiology. 44 (11): 2192–201. doi:10.1016/j.jacc.2004.08.058. PMID15582318.
↑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.
↑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.
↑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.
↑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.
↑Nicholas G, Thomas M, Langley B, Somers W, Patel K, Kemp CF, Sharma M, Kambadur R (Oct 2002). "Titin-cap associates with, and regulates secretion of, Myostatin". Journal of Cellular Physiology. 193 (1): 120–31. doi:10.1002/jcp.10158. PMID12209887.
↑ 34.034.1Frey N, Olson EN (Apr 2002). "Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins". The Journal of Biological Chemistry. 277 (16): 13998–4004. doi:10.1074/jbc.M200712200. PMID11842093.
↑Faulkner G, Pallavicini A, Comelli A, Salamon M, Bortoletto G, Ievolella C, Trevisan S, Kojic' S, Dalla Vecchia F, Laveder P, Valle G, Lanfranchi G (Dec 2000). "FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle". The Journal of Biological Chemistry. 275 (52): 41234–42. doi:10.1074/jbc.M007493200. PMID10984498.
↑Haworth RS, Cuello F, Herron TJ, Franzen G, Kentish JC, Gautel M, Avkiran M (Nov 2004). "Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function". Circulation Research. 95 (11): 1091–9. doi:10.1161/01.RES.0000149299.34793.3c. PMID15514163.
↑Mihatsch K, Nestler M, Saluz HP, Henke A, Munder T (Jan 2009). "Proapoptotic protein Siva binds to the muscle protein telethonin in cardiomyocytes during coxsackieviral infection". Cardiovascular Research. 81 (1): 108–15. doi:10.1093/cvr/cvn276. PMID18849585.
↑Zou P, Gautel M, Geerlof A, Wilmanns M, Koch MH, Svergun DI (Jan 2003). "Solution scattering suggests cross-linking function of telethonin in the complex with titin". The Journal of Biological Chemistry. 278 (4): 2636–44. doi:10.1074/jbc.M210217200. PMID12446666.
↑Mues A, van der Ven PF, Young P, Fürst DO, Gautel M (May 1998). "Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin". FEBS Letters. 428 (1–2): 111–4. doi:10.1016/s0014-5793(98)00501-8. PMID9645487.
Further reading
Faulkner G, Lanfranchi G, Valle G (May 2001). "Telethonin and other new proteins of the Z-disc of skeletal muscle". IUBMB Life. 51 (5): 275–82. doi:10.1080/152165401317190761. PMID11699871.
Mues A, van der Ven PF, Young P, Fürst DO, Gautel M (May 1998). "Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin". FEBS Letters. 428 (1–2): 111–4. doi:10.1016/S0014-5793(98)00501-8. PMID9645487.
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. doi:10.1038/27603. PMID9804419.
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.
Faulkner G, Pallavicini A, Comelli A, Salamon M, Bortoletto G, Ievolella C, Trevisan S, Kojic' S, Dalla Vecchia F, Laveder P, Valle G, Lanfranchi G (Dec 2000). "FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle". The Journal of Biological Chemistry. 275 (52): 41234–42. doi:10.1074/jbc.M007493200. PMID10984498.
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.
Frey N, Olson EN (Apr 2002). "Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins". The Journal of Biological Chemistry. 277 (16): 13998–4004. doi:10.1074/jbc.M200712200. PMID11842093.
Nicholas G, Thomas M, Langley B, Somers W, Patel K, Kemp CF, Sharma M, Kambadur R (Oct 2002). "Titin-cap associates with, and regulates secretion of, Myostatin". Journal of Cellular Physiology. 193 (1): 120–31. doi:10.1002/jcp.10158. PMID12209887.
Zou P, Gautel M, Geerlof A, Wilmanns M, Koch MH, Svergun DI (Jan 2003). "Solution scattering suggests cross-linking function of telethonin in the complex with titin". The Journal of Biological Chemistry. 278 (4): 2636–44. doi:10.1074/jbc.M210217200. PMID12446666.
Knöll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR (Dec 2002). "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy". Cell. 111 (7): 943–55. doi:10.1016/S0092-8674(02)01226-6. PMID12507422.
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.
Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knöll R, Hoshijima M, Chien KR, Kimura A (Dec 2004). "Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy". Journal of the American College of Cardiology. 44 (11): 2192–201. doi:10.1016/j.jacc.2004.08.058. PMID15582318.