Effects of the storage conditions on the stability of natural and synthetic cannabis in biological matrices for forensic toxicology analysis: An update from the literature
Contents
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Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | TCAP, CMD1N, LGMD2G, T-cap, TELE, telethonin, CMH25, titin-cap, LGMDR7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 604488; MGI: 1330233; HomoloGene: 2724; GeneCards: TCAP; OMA:TCAP - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
Structure
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]
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
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
Telethonin has been shown to interact with:
References
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- ^ 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.
- ^ Podobed PS, Alibhai FJ, Chow CW, Martino TA (2014). "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. Bibcode:2014PLoSO...9j4907P. doi:10.1371/journal.pone.0104907. PMC 4133362. PMID 25121604.
- ^ 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 (BBA) - Molecular Basis of Disease. 1588 (1): 33–40. doi:10.1016/s0925-4439(02)00113-8. PMID 12379311.
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- ^ Rampersaud E, Siegfried JD, Norton N, Li D, Martin E, Hershberger RE (Jan 2011). "Rare variant mutations identified in pediatric patients with dilated cardiomyopathy". Progress in Pediatric Cardiology. 31 (1): 39–47. doi:10.1016/j.ppedcard.2010.11.008. PMC 3072577. PMID 21483645.
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- ^ 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. PMID 15582318.
- ^ 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. PMID 11846417. S2CID 1824336.
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- ^ 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. PMID 15136035.
- ^ 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. PMID 17921333. S2CID 45084505.
- ^ 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.
- ^ 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. PMID 12209887. S2CID 8866409.
- ^ a b 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. PMID 11842093.
- ^ 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. PMID 10984498.
- ^ 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.
- ^ 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.
- ^ 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. PMID 12446666.
- ^ 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. PMID 9645487. S2CID 11786578.
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. PMID 11699871. S2CID 23688131.
- Moreira ES, Vainzof M, Marie SK, Sertié AL, Zatz M, Passos-Bueno MR (Jul 1997). "The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11-12". American Journal of Human Genetics. 61 (1): 151–9. doi:10.1086/513889. PMC 1715843. PMID 9245996.
- 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. PMID 9645487. S2CID 11786578.
- 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. PMID 9804419. S2CID 4426977.
- 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. PMID 10655062. S2CID 8698402.
- 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. PMID 10984498.
- 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. PMID 11763198. S2CID 22553971.
- 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. PMID 11842093.
- 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. PMID 12209887. S2CID 8866409.
- 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. PMID 12446666.
- 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. PMID 12507422. S2CID 15082967.
- 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. PMID 15010812.
- 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. PMID 15136035.
- 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. PMID 15582318.