TNNT1

Last updated
TNNT1
Identifiers
Aliases TNNT1 , ANM, NEM5, STNT, TNT, TNTS, troponin T1, slow skeletal type
External IDs OMIM: 191041 MGI: 1333868 HomoloGene: 20704 GeneCards: TNNT1
Orthologs
SpeciesHumanMouse
Entrez

7138

21955

Ensembl

ENSG00000105048

ENSMUSG00000064179

UniProt

P13805
Q3B759

O88346

RefSeq (mRNA)

NM_001126132
NM_001126133
NM_001291774
NM_003283

NM_001277903
NM_001277904
NM_011618
NM_001360154

RefSeq (protein)

NP_001119604
NP_001119605
NP_001278703
NP_003274

NP_001264832
NP_001264833
NP_035748
NP_001347083

Location (UCSC) Chr 19: 55.13 – 55.15 Mb Chr 7: 4.5 – 4.52 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Slow skeletal muscle troponin T (sTnT) is a protein that in humans is encoded by the TNNT1 gene. [5] [6]

Contents

The TNNT1 gene is located at 19q13.4 in the human chromosomal genome, encoding the slow twitch skeletal muscle isoform of troponin T (ssTnT). ssTnT is an ~32-kDa protein consisting of 262 amino acids (including the first methionine) with an isoelectric point (pI) of 5.95. It is the tropomyosin binding and thin filament anchoring subunit of the troponin complex in the sarcomeres of slow twitch skeletal muscle fibers. [7] [8] [9] TNNT1 gene is specifically expressed in slow skeletal muscle of vertebrates, with one exception that dry land toad (Bufo) cardiac muscle expresses ssTnT other than cardiac TnT. [10]

Evolution

TnT TnI gene pairs.jpg

Three homologous genes have evolved in vertebrates, encoding three muscle type specific isoforms of TnT. [9] Each of the TnT isoform genes is linked to one of the three troponin I [11] isoform genes encoding the inhibitory subunit of the troponin complex, in chromosomal DNA to form three gene pairs: The fast skeletal muscle TnI (fsTnI)-fsTnT, ssTnI-cardiac (cTnT) and cTnI-ssTnT gene pairs. Sequence and epitope conservation studies suggested that genes encoding the muscle type specific TnT and TnI isoforms may have evolved from duplications of a fsTnI-like-fsTnT-like gene pair. [12] Evolutionary lineage of the three TnI-TnT gene pairs shows that cTnI-ssTnT is the newest [12] and most closely linked. [13]

Protein sequence alignment demonstrated that TNNT1 genes are highly conserved among vertebrate species (Fig. 2), especially in the middle and C-terminal regions, while the three muscle type isoforms are significantly diverged among vertebrate species. [8] [9]

TNNT1 gene phylogenic tree.jpg

Alternative splicing

In mammalian and avian species, TNNT1 gene has a total of 14 exons, among which exon 5 encoding an 11-amino acid in the N-terminal region is alternatively spliced, generating a high molecular weight and a low molecular weight slow TnT splice forms (Jin, Chen et al. 1998). [14] [15] Biochemical studies showed that TnT splice forms have detectable different molecular conformation in the middle and C-terminal regions, producing different binding affinities for TnI and tropomyosin. [8] [9] The alternative splice forms of ssTnT play a role in skeletal muscle adaptation in physiologic and pathological conditions. [16] Alternative splicing at alternative acceptor sites of intron 5 generates a single amino acid difference in the N-terminal region of ssTnT, [15] of which functional significance has not been established.

Clinical significance

A nonsense mutation E180X in the exon 11 of TNNT1 gene causes Amish Nemaline Myopathy (ANM), which is a severe form of recessive nemaline myopathy originally found in the Old Order Amish population in Pennsylvania, USA. [17] [18] Truncation of the ssTnT polypeptide chain by the E180X mutation deletes the tropomyosin-binding site 2 [19] as well as the binding sites for TnI and troponin C (TnC) in the C-terminal region (Fig. 3). Consistent with the recessive phenotype, the truncated ssTnT is incapable of incorporation into the myofilaments and completely degraded in muscle cells. [20]

Skeletal troponin complex structure.tif

Tnnt1 gene targeted mouse studies reproduced the myopathic phenotypes of ANM. [21] [22] ssTnT null mice showed significantly decreased type I slow fibers in diaphragm and soleus muscles with hypertrophy of type II fast fibers, increased fatigability, and active regeneration of slow fibers (Wei, Lu et al. 2014). [21]

Recent case reports identified three more mutations in TNNT1 gene to cause nemaline myopathies outside the Amish population. A nonsense mutation S108X in exon 9 was identified in a Hispanic male patient with severe recessive nemaline myopathy phenotype. [23] A Dutch patient with compound heterozygous TNNT1 gene mutations that cause exon 8 and exon 14 deletions also presents nemaline myopathy phenotypes. [24] A rearrangement in TNNT1 gene (c.574_577 delins TAGTGCTGT) leading to aberrant splicing that causes C-terminal truncation of the protein (L203 truncation) was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited nemaline Myopathy. [25]

Illustrated in Fig. 3, the S108X mutation truncates ssTnT protein to cause a loss of functional structures equivalent to that of E180X. The exon 8 deletion destructs the middle region tropomyosin-binding site 1. [19] [26] The L203 truncation deletes the binding sites for TnI and TnC but preserves both tropomyosin-binding sites 1 and 2. [19] It remains to be investigated whether this novel mutation is able to bind the actin-tropomyosin thin filament in vivo and how it causes recessive nemaline myopathy.

Alternative splicing of exon 5 produces high and low molecular weight splice forms of ssTnT. The low molecular ssTnT was significantly upregulated in type 1 (demyelination) but not type 2 (axon loss) Charcot-Marie-Tooth disease, [16] suggesting that structural modification of TnT in the myofilaments may contribute to adaptation to abnormalities in neuronal activation.

Interactions

TNNT1 has been shown to interact with PRKG1. [27]

[28] [29] [30]

Notes

Related Research Articles

Troponin Protein complex

Troponin, or the troponin complex, is a complex of three regulatory proteins that are integral to muscle contraction in skeletal muscle and cardiac muscle, but not smooth muscle. Measurements of cardiac-specific troponins I and T are extensively used as diagnostic and prognostic indicators in the management of myocardial infarction and acute coronary syndrome. Blood troponin levels may be used as a diagnostic marker for stroke, although the sensitivity of this measurement is low.

Titin Mammalian protein found in Homo sapiens

Titin, also known as connectin, is a protein that in humans is encoded by the TTN gene. Titin is a giant protein, greater than 1 µm in length, that functions as a molecular spring which is responsible for the passive elasticity of muscle. It comprises 244 individually folded protein domains connected by unstructured peptide sequences. These domains unfold when the protein is stretched and refold when the tension is removed.

Tropomyosin Protein

Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in actin-based cytoskeletons.

Nemaline myopathy is a congenital, often hereditary neuromuscular disorder with many symptoms that can occur such as muscle weakness, hypoventilation, swallowing dysfunction, and impaired speech ability. The severity of these symptoms varies and can change throughout one's life to some extent. The prevalence is estimated at 1 in 50,000 live births. It is the most common non-dystrophic myopathy.

Troponin C Protein family

Troponin C is a protein which is part of the troponin complex. It contains four calcium-binding EF hands, although different isoforms may have fewer than four functional calcium-binding subdomains. It is a component of thin filaments, along with actin and tropomyosin. It contains an N lobe and a C lobe. The C lobe serves a structural purpose and binds to the N domain of troponin I (TnI). The C lobe can bind either Ca2+ or Mg2+. The N lobe, which binds only Ca2+, is the regulatory lobe and binds to the C domain of troponin I after calcium binding.

Troponin T Protein family

Troponin T is a part of the troponin complex, which are proteins integral to the contraction of skeletal and heart muscles. They are expressed in skeletal and cardiac myocytes. Troponin T binds to tropomyosin and helps position it on actin, and together with the rest of the troponin complex, modulates contraction of striated muscle. The cardiac subtype of troponin T is especially useful in the laboratory diagnosis of heart attack because it is released into the blood-stream when damage to heart muscle occurs. It was discovered by the German physician Hugo A. Katus at the University of Heidelberg, who also developed the troponin T assay.

Troponin I Protein family

Troponin I is a cardiac and skeletal muscle protein family. It is a part of the troponin protein complex, where it binds to actin in thin myofilaments to hold the actin-tropomyosin complex in place. Troponin I prevents myosin from binding to actin in relaxed muscle. When calcium binds to the troponin C, it causes conformational changes which lead to dislocation of troponin I. Afterwards, tropomyosin leaves the binding site for myosin on actin leading to contraction of muscle. The letter I is given due to its inhibitory character. It is a useful marker in the laboratory diagnosis of heart attack. It occurs in different plasma concentration but the same circumstances as troponin T - either test can be performed for confirmation of cardiac muscle damage and laboratories usually offer one test or the other.

An exonic splicing silencer (ESS) is a short region of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing of the pre-mRNA and contribute to constitutive and alternate splicing. To elicit the silencing affect, ESSs recruit proteins that will negatively affect the core splicing machinery.

TNNI3

Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3 gene. It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

TNNT2

Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.

TPM1

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

Tropomyosin 3

Tropomyosin alpha-3 chain is a protein that in humans is encoded by the TPM3 gene.

Troponin C type 1

Troponin C, also known as TN-C or TnC, is a protein that resides in the troponin complex on actin thin filaments of striated muscle and is responsible for binding calcium to activate muscle contraction. Troponin C is encoded by the TNNC1 gene in humans for both cardiac and slow skeletal muscle.

TPM2

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

TNNI1

Troponin I, slow skeletal muscle is a protein that in humans is encoded by the TNNI1 gene. It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

TNNI2

Troponin I, fast skeletal muscle is a protein that in humans is encoded by the TNNI2 gene.

TNNT3

Fast skeletal muscle troponin T (fTnT) is a protein that in humans is encoded by the TNNT3 gene.

TNNC2

Troponin C, skeletal muscle is a protein that in humans is encoded by the TNNC2 gene.

ENO3

Enolase 3 (ENO3), more commonly known as beta-enolase (ENO-β), is an enzyme that in humans is encoded by the ENO3 gene.

Cofilin-2

Cofilin 2 (muscle) also known as CFL2 is a protein which in humans is encoded by the CFL2 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000105048 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000064179 - Ensembl, 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. ↑ Samson F, de Jong PJ, Trask BJ, Koza-Taylor P, Speer MC, Potter T, Roses AD, Gilbert JR (Aug 1992). "Assignment of the human slow skeletal troponin T gene to 19q13.4 using somatic cell hybrids and fluorescence in situ hybridization analysis". Genomics. 13 (4): 1374–5. doi:10.1016/0888-7543(92)90077-6. PMID   1505979.
  6. ↑ "Entrez Gene: TNNT1 troponin T type 1 (skeletal, slow)".
  7. ↑ Perry SV (Aug 1998). "Troponin T: genetics, properties and function". Journal of Muscle Research and Cell Motility. 19 (6): 575–602. doi:10.1023/a:1005397501968. PMID   9742444. S2CID   1882224.
  8. 1 2 3 Jin JP, Zhang Z, Bautista JA (2008). "Isoform diversity, regulation, and functional adaptation of troponin and calponin". Critical Reviews in Eukaryotic Gene Expression. 18 (2): 93–124. doi:10.1615/critreveukargeneexpr.v18.i2.10. PMID   18304026.
  9. 1 2 3 4 Wei B, Jin JP (Jan 2011). "Troponin T isoforms and posttranscriptional modifications: Evolution, regulation and function". Archives of Biochemistry and Biophysics. 505 (2): 144–54. doi:10.1016/j.abb.2010.10.013. PMC   3018564 . PMID   20965144.
  10. ↑ Feng HZ, Chen X, Hossain MM, Jin JP (Aug 2012). "Toad heart utilizes exclusively slow skeletal muscle troponin T: an evolutionary adaptation with potential functional benefits". The Journal of Biological Chemistry. 287 (35): 29753–64. doi: 10.1074/jbc.M112.373191 . PMC   3436204 . PMID   22778265.
  11. ↑ Dweck D, Sanchez-Gonzalez MA, Chang AN, Dulce RA, Badger CD, Koutnik AP, Ruiz EL, Griffin B, Liang J, Kabbaj M, Fincham FD, Hare JM, Overton JM, Pinto JR (Aug 2014). "Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy". The Journal of Biological Chemistry. 289 (33): 23097–111. doi: 10.1074/jbc.M114.561472 . PMC   4132808 . PMID   24973218.
  12. 1 2 Chong SM, Jin JP (May 2009). "To investigate protein evolution by detecting suppressed epitope structures". Journal of Molecular Evolution. 68 (5): 448–60. Bibcode:2009JMolE..68..448C. doi:10.1007/s00239-009-9202-0. PMC   2752406 . PMID   19365646.
  13. ↑ Huang QQ, Jin JP (Dec 1999). "Preserved close linkage between the genes encoding troponin I and troponin T, reflecting an evolution of adapter proteins coupling the Ca(2+) signaling of contractility". Journal of Molecular Evolution. 49 (6): 780–8. Bibcode:1999JMolE..49..780H. doi:10.1007/pl00006600. PMID   10594179. S2CID   9839814.
  14. ↑ Gahlmann R, Troutt AB, Wade RP, Gunning P, Kedes L (Nov 1987). "Alternative splicing generates variants in important functional domains of human slow skeletal troponin T". The Journal of Biological Chemistry. 262 (33): 16122–6. doi: 10.1016/S0021-9258(18)47705-8 . PMID   2824479.
  15. 1 2 Huang QQ, Chen A, Jin JP (Mar 1999). "Genomic sequence and structural organization of mouse slow skeletal muscle troponin T gene". Gene. 229 (1–2): 1–10. doi:10.1016/s0378-1119(99)00051-7. PMID   10095098.
  16. 1 2 Larsson L, Wang X, Yu F, Höök P, Borg K, Chong SM, Jin JP (Sep 2008). "Adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease". American Journal of Physiology. Cell Physiology. 295 (3): C722–31. doi:10.1152/ajpcell.00110.2008. PMC   2544436 . PMID   18579801.
  17. ↑ Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, Koch T, Schäffer AA, Francomano CA, Biesecker LG (Oct 2000). "A novel nemaline myopathy in the Amish caused by a mutation in troponin T1". American Journal of Human Genetics. 67 (4): 814–21. doi:10.1086/303089. PMC   1287886 . PMID   10952871.
  18. ↑ Jin JP, Brotto MA, Hossain MM, Huang QQ, Brotto LS, Nosek TM, Morton DH, Crawford TO (Jul 2003). "Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy". The Journal of Biological Chemistry. 278 (28): 26159–65. doi: 10.1074/jbc.M303469200 . PMID   12732643.
  19. 1 2 3 Jin JP, Chong SM (Aug 2010). "Localization of the two tropomyosin-binding sites of troponin T". Archives of Biochemistry and Biophysics. 500 (2): 144–50. doi:10.1016/j.abb.2010.06.001. PMC   2904419 . PMID   20529660.
  20. ↑ Martin AF (Jan 1981). "Turnover of cardiac troponin subunits. Kinetic evidence for a precursor pool of troponin-I". The Journal of Biological Chemistry. 256 (2): 964–8. doi: 10.1016/S0021-9258(19)70073-8 . PMID   7451483.
  21. 1 2 Feng HZ, Wei B, Jin JP (Nov 2009). "Deletion of a genomic segment containing the cardiac troponin I gene knocks down expression of the slow troponin T gene and impairs fatigue tolerance of diaphragm muscle". The Journal of Biological Chemistry. 284 (46): 31798–806. doi: 10.1074/jbc.M109.020826 . PMC   2797250 . PMID   19797054.
  22. ↑ Wei B, Lu Y, Jin JP (Mar 2014). "Deficiency of slow skeletal muscle troponin T causes atrophy of type I slow fibres and decreases tolerance to fatigue". The Journal of Physiology. 592 (Pt 6): 1367–80. doi:10.1113/jphysiol.2013.268177. PMC   3961093 . PMID   24445317.
  23. ↑ Marra JD, Engelstad KE, Ankala A, Tanji K, Dastgir J, De Vivo DC, Coffee B, Chiriboga CA (May 2015). "Identification of a novel nemaline myopathy-causing mutation in the troponin T1 (TNNT1) gene: a case outside of the old order Amish". Muscle & Nerve. 51 (5): 767–72. doi:10.1002/mus.24528. PMID   25430424. S2CID   29391961.
  24. ↑ van der Pol WL, Leijenaar JF, Spliet WG, Lavrijsen SW, Jansen NJ, Braun KP, Mulder M, Timmers-Raaijmakers B, Ratsma K, Dooijes D, van Haelst MM (Mar 2014). "Nemaline myopathy caused byTNNT1 mutations in a Dutch pedigree". Molecular Genetics & Genomic Medicine. 2 (2): 134–7. doi:10.1002/mgg3.52. PMC   3960055 . PMID   24689076.
  25. ↑ Abdulhaq UN, Daana M, Dor T, Fellig Y, Eylon S, Schuelke M, Shaag A, Elpeleg O, Edvardson S (2015). "Nemaline body myopathy caused by a novel mutation in Troponin T1 (TNNT1)". Muscle Nerve. 53 (4): 564–9. doi:10.1002/mus.24885. PMID   26296490. S2CID   41713544.
  26. ↑ Amarasinghe C, Jin JP (Jun 2015). "N-Terminal Hypervariable Region of Muscle Type Isoforms of Troponin T Differentially Modulates the Affinity of Tropomyosin-Binding Site 1". Biochemistry. 54 (24): 3822–30. doi:10.1021/acs.biochem.5b00348. PMID   26024675.
  27. ↑ Yuasa K, Michibata H, Omori K, Yanaka N (Dec 1999). "A novel interaction of cGMP-dependent protein kinase I with troponin T". The Journal of Biological Chemistry. 274 (52): 37429–34. doi: 10.1074/jbc.274.52.37429 . PMID   10601315.
  28. ↑ Jin JP, Chen A, Huang QQ (Jul 1998). "Three alternatively spliced mouse slow skeletal muscle troponin T isoforms: conserved primary structure and regulated expression during postnatal development". Gene. 214 (1–2): 121–9. doi:10.1016/s0378-1119(98)00214-5. PMID   9651500.
  29. ↑ Palm T, Graboski S, Hitchcock-DeGregori SE, Greenfield NJ (Nov 2001). "Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region". Biophysical Journal. 81 (5): 2827–37. Bibcode:2001BpJ....81.2827P. doi:10.1016/S0006-3495(01)75924-3. PMC   1301748 . PMID   11606294.
  30. ↑ Vinogradova MV, Stone DB, Malanina GG, Karatzaferi C, Cooke R, Mendelson RA, Fletterick RJ (Apr 2005). "Ca(2+)-regulated structural changes in troponin". Proceedings of the National Academy of Sciences of the United States of America. 102 (14): 5038–43. Bibcode:2005PNAS..102.5038V. doi: 10.1073/pnas.0408882102 . PMC   555973 . PMID   15784741.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.