Telethonin, also known as Tcap, is a protein that in humans is encoded by the TCAP gene.[5][6][7] 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.

TCAP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTCAP, CMD1N, LGMD2G, T-cap, TELE, telethonin, CMH25, titin-cap, LGMDR7
External IDsOMIM: 604488; MGI: 1330233; HomoloGene: 2724; GeneCards: TCAP; OMA:TCAP - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_003673

NM_011540

RefSeq (protein)

NP_003664
NP_003664.1

NP_035670

Location (UCSC)Chr 17: 39.67 – 39.67 MbChr 11: 98.27 – 98.28 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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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

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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]

Telethonin is a substrate of titin kinase,[18] protein kinase D (PKD) and CaM Kinase II.[19] 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.[20] 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.[19]

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]

Clinical Significance

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Mutations in this gene are associated with limb-girdle muscular dystrophy type R7 (previously 2G),[24] hypertrophic cardiomyopathy,[25][26][27] dilated cardiomyopathy,[28][29] idiopathic cardiomyopathy,[30] and gastrointestinal smooth muscle-related diseases.[15]

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.[31] Mutations in Titin associated with dilated cardiomyopathy, including Val54Met, 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, Trp4Arg, 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, Thr326Ile, showed decreased binding to Telethonin and increased extracellular secretion.[33]

Interactions

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Telethonin has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000173991Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000007877Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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. hdl:11577/2469154. PMID 9350988. S2CID 1482856.
  6. ^ a b Gregorio CC, Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S (Nov 1998). "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. doi:10.1083/jcb.143.4.1013. PMC 2132961. PMID 9817758.
  7. ^ "Entrez Gene: TCAP titin-cap (telethonin)".
  8. ^ "Protein Information for the human TCAP gene (Uniprot ID: O15273)". COPaKB: Cardiac Organellar Protein Atlas Knowledgebase. Retrieved 20 June 2015.
  9. ^ 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. Bibcode:2006Natur.439..229Z. doi:10.1038/nature04343. PMID 16407954. S2CID 7509846.
  10. ^ 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. PMID 16713295.
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  21. ^ 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. PMID 16678796..
  22. ^ 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. PMID 18849585.
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  40. ^ 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. PMID 15514163.
  41. ^ 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. PMID 18849585.
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Further reading

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