Telethonin Explained

Telethonin, also known as Tcap, is a protein that in humans is encoded by the TCAP gene.[1] [2] [3] Telethonin is expressed in cardiac and skeletal muscle at Z-discs and functions to regulate sarcomere assembly, T-tubule function and apoptosis. Telethonin has been implicated in several diseases, including limb-girdle muscular dystrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy and idiopathic cardiomyopathy.

Structure

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 muscle LIM protein (MLP) at sarcomere 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]

Telethonin is a substrate of titin kinase, protein kinase D (PKD) and CaM Kinase II.[14] Telethonin, as well as TNNI3, MYBPC3 and MYOM2 are phosphorylated by PKD in cardiomyocytes, and this leads to a reduction in calcium sensitivity of myofilaments, as well as accelerated crossbridge kinetics.[15] Bis-phosphorylation of Telethonin specifically at sites Serine-157 and Serine-161 has been shown to be essential for normal T-tubule organization and intracellular calcium transient kinetics.[14]

The intracellular degradation of Telethonin is regulated by MDM2 in a proteasomal-dependent yet ubiquitin-independent manner.[16] 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[17]

Telethonin was also identified to be targeted and regulated by transcriptional activators CLOCK and BMAL1, thus demonstrating that TCAP is a circadian regulated gene.[18]

Clinical Significance

Mutations in this gene are associated with limb-girdle muscular dystrophy type R7 (previously 2G),[19] hypertrophic cardiomyopathy,[20] [21] [22] dilated cardiomyopathy,[23] [24] idiopathic cardiomyopathy,[25] and gastrointestinal smooth muscle-related diseases.[11]

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.[26] Mutations in Titin associated with dilated cardiomyopathy, including Val54Met, have been shown specifically to impair binding of Titin with Telethonin.[27] 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.[28]

Interactions

Telethonin has been shown to interact with:

Further reading

External links

Notes and References

  1. Valle G, Faulkner G, De Antoni A, Pacchioni B, Pallavicini A, Pandolfo D, Tiso N, Toppo S, Trevisan S, Lanfranchi G . Telethonin, a novel sarcomeric protein of heart and skeletal muscle . FEBS Letters . 415 . 2 . 163–8 . Sep 1997 . 9350988 . 10.1016/S0014-5793(97)01108-3 . 1482856 . free . 11577/2469154 . free .
  2. Gregorio CC, Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S . The NH2 terminus of titin spans the Z-disc: its interaction with a novel 19-kD ligand (T-cap) is required for sarcomeric integrity . The Journal of Cell Biology . 143 . 4 . 1013–27 . Nov 1998 . 9817758 . 2132961 . 10.1083/jcb.143.4.1013 .
  3. Web site: Entrez Gene: TCAP titin-cap (telethonin).
  4. Web site: Protein Information for the human TCAP gene (Uniprot ID: O15273). COPaKB: Cardiac Organellar Protein Atlas Knowledgebase. 20 June 2015.
  5. Zou P, Pinotsis N, Lange S, Song YH, Popov A, Mavridis I, Mayans OM, Gautel M, Wilmanns M . Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk . Nature . 439 . 7073 . 229–33 . Jan 2006 . 16407954 . 10.1038/nature04343 . 2006Natur.439..229Z . 7509846 .
  6. Pinotsis N, Petoukhov M, Lange S, Svergun D, Zou P, Gautel M, Wilmanns M . Evidence for a dimeric assembly of two titin/telethonin complexes induced by the telethonin C-terminus . Journal of Structural Biology . 155 . 2 . 239–50 . Aug 2006 . 16713295 . 10.1016/j.jsb.2006.03.028 .
  7. Mason P, Bayol S, Loughna PT . The novel sarcomeric protein telethonin exhibits developmental and functional regulation . Biochemical and Biophysical Research Communications . 257 . 3 . 699–703 . Apr 1999 . 10208846 . 10.1006/bbrc.1999.0531 .
  8. White J, Barro MV, Makarenkova HP, Sanger JW, Sanger JM . Localization of sarcomeric proteins during myofibril assembly in cultured mouse primary skeletal myotubes . Anatomical Record . 297 . 9 . 1571–84 . Sep 2014 . 25125171 . 10.1002/ar.22981 . 4145531.
  9. 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 . 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 . Dec 2002 . 12507422 . 10.1016/s0092-8674(02)01226-6. 15082967 . free .
  10. Furukawa T, Ono Y, Tsuchiya H, Katayama Y, Bang ML, Labeit D, Labeit S, Inagaki N, Gregorio CC . 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 . Nov 2001 . 11697903 . 10.1006/jmbi.2001.5053 .
  11. Mazzone A, Strege PR, Tester DJ, Bernard CE, Faulkner G, De Giorgio R, Makielski JC, Stanghellini V, Gibbons SJ, Ackerman MJ, Farrugia G . A mutation in telethonin alters Nav1.5 function . The Journal of Biological Chemistry . 283 . 24 . 16537–44 . Jun 2008 . 18408010 . 10.1074/jbc.M801744200 . 2423252. free .
  12. Knöll R, Linke WA, Zou P, Miocic S, Kostin S, Buyandelger B, Ku CH, Neef S, Bug M, Schäfer K, Knöll G, Felkin LE, Wessels J, Toischer K, Hagn F, Kessler H, Didié M, Quentin T, Maier LS, Teucher N, Unsöld B, Schmidt A, Birks EJ, Gunkel S, Lang P, Granzier H, Zimmermann WH, Field LJ, Faulkner G, Dobbelstein M, Barton PJ, Sattler M, Wilmanns M, Chien KR . Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart . Circulation Research . 109 . 7 . 758–69 . Sep 2011 . 21799151 . 10.1161/CIRCRESAHA.111.245787 . 3664427.
  13. Ibrahim M, Siedlecka U, Buyandelger B, Harada M, Rao C, Moshkov A, Bhargava A, Schneider M, Yacoub MH, Gorelik J, Knöll R, Terracciano CM . A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart . Human Molecular Genetics . 22 . 2 . 372–83 . Jan 2013 . 23100327 . 10.1093/hmg/dds434 . 3526164.
  14. Candasamy AJ, Haworth RS, Cuello F, Ibrahim M, Aravamudhan S, Krüger M, Holt MR, Terracciano CM, Mayr M, Gautel M, Avkiran M . Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes . The Journal of Biological Chemistry . 289 . 3 . 1282–93 . Jan 2014 . 24280220 . 10.1074/jbc.M113.479030 . 3894314. free .
  15. Haworth RS, Cuello F, Herron TJ, Franzen G, Kentish JC, Gautel M, Avkiran M . Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function . Circulation Research . 95 . 11 . 1091–9 . Nov 2004 . 15514163 . 10.1161/01.RES.0000149299.34793.3c . free .
  16. 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 . MDM2 interacts with and downregulates a sarcomeric protein, TCAP . Biochemical and Biophysical Research Communications . 345 . 1 . 355–61 . Jun 2006 . 16678796 . 10.1016/j.bbrc.2006.04.108 . .
  17. Mihatsch K, Nestler M, Saluz HP, Henke A, Munder T . Proapoptotic protein Siva binds to the muscle protein telethonin in cardiomyocytes during coxsackieviral infection . Cardiovascular Research . 81 . 1 . 108–15 . Jan 2009 . 18849585 . 10.1093/cvr/cvn276 . free .
  18. Podobed PS, Alibhai FJ, Chow CW, Martino TA . Circadian regulation of myocardial sarcomeric Titin-cap (Tcap, telethonin): identification of cardiac clock-controlled genes using open access bioinformatics data . PLOS ONE . 9 . 8 . e104907 . 2014 . 25121604 . 10.1371/journal.pone.0104907 . 4133362. 2014PLoSO...9j4907P . free .
  19. 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 . Telethonin protein expression in neuromuscular disorders . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1588 . 1 . 33–40 . Oct 2002 . 12379311 . 10.1016/s0925-4439(02)00113-8. free .
  20. Andersen PS, Havndrup O, Hougs L, Sørensen KM, Jensen M, Larsen LA, Hedley P, Thomsen AR, Moolman-Smook J, Christiansen M, Bundgaard H . 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 . Mar 2009 . 19035361 . 10.1002/humu.20862 . 30898294 .
  21. Bos JM, Poley RN, Ny M, Tester DJ, Xu X, Vatta M, Towbin JA, Gersh BJ, Ommen SR, Ackerman MJ . Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin . Molecular Genetics and Metabolism . 88 . 1 . 78–85 . May 2006 . 16352453 . 10.1016/j.ymgme.2005.10.008 . 2756511.
  22. Theis JL, Bos JM, Bartleson VB, Will ML, Binder J, Vatta M, Towbin JA, Gersh BJ, Ommen SR, Ackerman MJ . Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy . Biochemical and Biophysical Research Communications . 351 . 4 . 896–902 . Dec 2006 . 17097056 . 10.1016/j.bbrc.2006.10.119 .
  23. Rampersaud E, Siegfried JD, Norton N, Li D, Martin E, Hershberger RE . Rare variant mutations identified in pediatric patients with dilated cardiomyopathy . Progress in Pediatric Cardiology . 31 . 1 . 39–47 . Jan 2011 . 21483645 . 10.1016/j.ppedcard.2010.11.008 . 3072577.
  24. Hirtle-Lewis M, Desbiens K, Ruel I, Rudzicz N, Genest J, Engert JC, Giannetti N . The genetics of dilated cardiomyopathy: a prioritized candidate gene study of LMNA, TNNT2, TCAP, and PLN . Clinical Cardiology . 36 . 10 . 628–33 . Oct 2013 . 24037902 . 10.1002/clc.22193 . 6649360 .
  25. Hershberger RE, Parks SB, Kushner JD, Li D, Ludwigsen S, Jakobs P, Nauman D, Burgess D, Partain J, Litt M . Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy . Clinical and Translational Science . 1 . 1 . 21–6 . May 2008 . 19412328 . 10.1111/j.1752-8062.2008.00017.x . 2633921.
  26. 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 . Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy . Journal of the American College of Cardiology . 44 . 11 . 2192–201 . Dec 2004 . 15582318 . 10.1016/j.jacc.2004.08.058 . free .
  27. 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 . 1824336 . Titin mutations as the molecular basis for dilated cardiomyopathy . Biochemical and Biophysical Research Communications . 291 . 2 . 385–93 . Feb 2002 . 11846417 . 10.1006/bbrc.2002.6448 .
  28. 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 . 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 . Dec 2007 . 17921333 . 10.1152/ajpheart.00311.2007 . 45084505 .
  29. Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G . The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle . Journal of Molecular Biology . 339 . 2 . 313–25 . May 2004 . 15136035 . 10.1016/j.jmb.2004.03.071 .
  30. 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 . 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 . Dec 2007 . 17921333 . 10.1152/ajpheart.00311.2007 . 45084505 .
  31. 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 . MDM2 interacts with and downregulates a sarcomeric protein, TCAP . Biochemical and Biophysical Research Communications . 345 . 1 . 355–61 . Jun 2006 . 16678796 . 10.1016/j.bbrc.2006.04.108 .
  32. Nicholas G, Thomas M, Langley B, Somers W, Patel K, Kemp CF, Sharma M, Kambadur R . Titin-cap associates with, and regulates secretion of, Myostatin . Journal of Cellular Physiology . 193 . 1 . 120–31 . Oct 2002 . 12209887 . 10.1002/jcp.10158 . 8866409 .
  33. Frey N, Olson EN . 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 . Apr 2002 . 11842093 . 10.1074/jbc.M200712200 . free .
  34. 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 . FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle . The Journal of Biological Chemistry . 275 . 52 . 41234–42 . Dec 2000 . 10984498 . 10.1074/jbc.M007493200 . free .
  35. Haworth RS, Cuello F, Herron TJ, Franzen G, Kentish JC, Gautel M, Avkiran M . Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function . Circulation Research . 95 . 11 . 1091–9 . Nov 2004 . 15514163 . 10.1161/01.RES.0000149299.34793.3c . free .
  36. Mihatsch K, Nestler M, Saluz HP, Henke A, Munder T . Proapoptotic protein Siva binds to the muscle protein telethonin in cardiomyocytes during coxsackieviral infection . Cardiovascular Research . 81 . 1 . 108–15 . Jan 2009 . 18849585 . 10.1093/cvr/cvn276 . free .
  37. Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M . Structural basis for activation of the titin kinase domain during myofibrillogenesis . Nature . 395 . 6705 . 863–9 . Oct 1998 . 9804419 . 10.1038/27603 . 1998Natur.395..863M . 4426977 .
  38. Zou P, Gautel M, Geerlof A, Wilmanns M, Koch MH, Svergun DI . Solution scattering suggests cross-linking function of telethonin in the complex with titin . The Journal of Biological Chemistry . 278 . 4 . 2636–44 . Jan 2003 . 12446666 . 10.1074/jbc.M210217200 . free .
  39. Mues A, van der Ven PF, Young P, Fürst DO, Gautel M . 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 . May 1998 . 9645487 . 10.1016/s0014-5793(98)00501-8. 11786578 . free .

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