TNNT3

Last updated
TNNT3
Identifiers
Aliases TNNT3 , TNTF, troponin T3, fast skeletal type, beta-TnTF, DA2B2
External IDs OMIM: 600692; MGI: 109550; HomoloGene: 31405; GeneCards: TNNT3; OMA:TNNT3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7140

21957

Ensembl

ENSG00000130595
ENSG00000288250

ENSMUSG00000061723

UniProt

P45378

Q9QZ47

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC) Chr 11: 1.92 – 1.94 Mb Chr 7: 142.5 – 142.52 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Fast skeletal muscle troponin T (fTnT) is a protein that in humans is encoded by the TNNT3 gene. [5] [6]

The TNNT3 gene is located at 11p15.5 in the human genome, encoding the fast skeletal muscle isoform of troponin T (fsTnT). fsTnT is an ~31-kDa protein consisting of 268 amino acids including the first methionine with an isoelectric point (pI) of 6.21 (embryonic form). fsTnT is the tropomyosin-binding and thin filament anchoring subunit of the troponin complex in the sarcomeres of fast twitch skeletal muscle. [7] [8] [9] TNNT3 gene is specifically expressed in vertebrate fast twitch skeletal muscles. [8] [9] [10]

Evolution

TNNT3 gene phylogenic tree.jpg

TNNT3 gene evolved as one of the three TnT isoform genes in vertebrates. Each of the TnT isoform genes is linked to an upstream troponin I (TnI, one of the other two subunits of the troponin complex) isoform gene, and fsTnT is linked with fsTnI genes (Fig. 1). Sequence homology and protein epitope allosteric similarity data suggest that TnT gene was originated by duplication of a TnI-like ancestor gene and fsTnT was the first TnT emerged. [11] Whereas significantly diverged from the slow skeletal muscle TnT (ssTnT encoded by TNNT1) and cardiac TnT (cTnT encoded by TNNT2), Structure of fsTnT is conserved among vertebrate species (Fig. 2), reflecting specialized functional features of the different muscle fiber types. [7] [8] [9]

TnT TnI gene pairs.jpg

Alternative splicing

Mammalian TNNT3 gene contains 19 exons. Alternative RNA splicing of 8 of them significantly increases structural variations of fsTnT. [12] Two variable regions of the fsTnT protein are generated by alternative splicing (Fig. 3).

In the N-terminal region of fsTnT, exons 4, 5, 6, 7 and 8 are alternatively spliced in adult skeletal muscle cells. [12] [13] [14] A fetal fsTnT exon located between exons 8 and 9 is specifically expressed in embryonic muscle (Briggs and Schachat 1993). Exons 16 and 17, previously designated as α and β exons, in the C-terminal region of fsTnT are alternatively spliced in a mutually exclusive manner. [15]

Avian Tnnt3 gene has evolved with additional alternatively spliced exons, w, P1-7(x) and y, encoding the N-terminal variable region (Fig. 3). [16] [17] [18] Reflecting the power of combined alternative splicing of multiple exons to generate fsTnT variants, two-dimensional gel electrophoresis detected more than 40 different fsTnT splice forms in chicken leg muscle. [19]

Developmental regulation

Alternative splicing of FsTnT.jpg

Through alternative splicing of the fetal exon and other alternative exons in the N-terminal variable region, the expression of fsTnT during mammalian and avian development undergoes a high molecular to low molecular weight isoform switch in both fast and slow fiber dominant skeletal muscles. [20] The inclusion of more N-terminal exons increases the negative charge that tunes the overall molecular conformation of fsTnT and alters interaction with TnI, TnC and tropomyosin. [21] [22] [23] The alternative splicing-based addition of N-terminal negative charge in fsTnT also contributes to the tolerance to acidosis. [24]

Alternative splicing of the two C-terminal mutually exclusive exons 16 and 17 appears also regulated during development. [14] Exon 17 with a sequence more similar to the counterpart segment in ssTnT and cTnT is predominantly expressed in embryonic and neonatal fsTnT. [14] [25] Exon 16 of fsTnT was only found in adult skeletal muscles. Exons 16 and 17 both encode a 14 amino acids peptide fragment residing in the α-helix interfacing with TnI and TnC. Protein interaction studies revealed that incorporation of exon 17 weakened binding of fsTnT to TnC and tropomyosin. [26] Therefore, alternative splicing of exons 16 and 17 regulates the binding of fsTnT with TnI, possibly TnC, and thus tunes the function of the troponin complex and skeletal muscle contractility during development.

Avian Tnnt3 gene with additional alternatively spliced exons has unique expression pattern. The seven P exons are specifically expressed in pectoral muscles but not leg muscles. [24] During post hatch development of the avian pectoral muscles, the segment encoded by the P exons (named Tx from the original annotation of the coding exons as an x exon) is up-regulated and included predominantly in fsTnT of adult pectoral muscles. [27] Each P exon encodes a pentapeptide AHH(A/E)A. The Tx segment of adult fsTnT in avian orders of Galliformes and Craciformes contains 7-9 H(A/E)AAH repeats that possess high affinity binding to transition metal ions Cu(II), Ni(II), Zn(II) and Co(II). [27] The Tx segment of chicken breast muscle fsTnT also a binding capacity for calcium, presumably serves as a calcium reservoir in avian fast pectoral muscles. [28] Together with more N-terminal negative charges, this function may contribute to the higher calcium sensitivity of chicken breast muscle than that of leg muscle. [29]

The switch of high to low molecular weight splice forms occurs in avian leg muscles during post hatching development similar to that in developing mammalian skeletal muscles. Early during post hatch development of chicken pectoral muscles, fsTnT also shows a high to low molecular weight switch. However, around 28 days after hatch, fsTnT with Tx segment spliced-in is rapidly up-regulated and becomes the major fsTnT splice form in adult pectoral muscles. [27]

Deficiency of ssTnT did not affect the developmental switch of fsTnT splice forms in ssTnT-null mice, indicating that the developmental alternative splicing of the fsTnT pre-mRNA is regulated independent of skeletal muscle fiber type abnormality and adaptation. [20]

Notes

Related Research Articles

<span class="mw-page-title-main">Troponin</span> 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 myocarditis, myocardial infarction and acute coronary syndrome. Blood troponin levels may be used as a diagnostic marker for stroke or other myocardial injury that is ongoing, although the sensitivity of this measurement is low.

<span class="mw-page-title-main">Tropomyosin</span> Protein

Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It is present in smooth and striated muscle tissues, which can be found in various organs and body systems, including the heart, blood vessels, respiratory system, and digestive system. In fungi, tropomyosin is found in cell walls and helps maintain the structural integrity of cells.

<span class="mw-page-title-main">PAX3</span> Paired box gene 3

The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.

<span class="mw-page-title-main">Tropomodulin</span>

Tropomodulin (TMOD) is a protein which binds and caps the minus end of actin, regulating the length of actin filaments in muscle and non-muscle cells.

<span class="mw-page-title-main">Actin, alpha skeletal muscle</span> Protein-coding gene in the species Homo sapiens

Actin, alpha skeletal muscle is a protein that in humans is encoded by the ACTA1 gene.

<span class="mw-page-title-main">TNNI3</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">TNNT2</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">TPM1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Tropomyosin 3</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">Troponin C type 1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">TPM2</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">TNNI1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">TNNI2</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">TNNT1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">RBM4</span> Protein-coding gene in the species Homo sapiens

RNA-binding protein 4 is a protein that in humans is encoded by the RBM4 gene.

<span class="mw-page-title-main">AMPD3</span> Protein-coding gene in the species Homo sapiens

AMP deaminase 3 is an enzyme that in humans is encoded by the AMPD3 gene.

<span class="mw-page-title-main">Troponin C, skeletal muscle</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Ankyrin-1</span> Protein-coding gene in the species Homo sapiens

Ankyrin 1, also known as ANK-1, and erythrocyte ankyrin, is a protein that in humans is encoded by the ANK1 gene.

<span class="mw-page-title-main">Tropomodulin 4</span> Protein-coding gene in the species Homo sapiens

Tropomodulin 4 (muscle) also known as TMOD4 is a protein which in humans is encoded by the TMOD4 gene.

<span class="mw-page-title-main">Calponin 1</span> Protein found in humans

Calponin 1 is a basic smooth muscle protein that in humans is encoded by the CNN1 gene.

References

  1. 1 2 3 ENSG00000288250 GRCh38: Ensembl release 89: ENSG00000130595, ENSG00000288250 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000061723 – 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. ↑ Wu QL, Jha PK, Raychowdhury MK, Du Y, Leavis PC, Sarkar S (Jun 1994). "Isolation and characterization of human fast skeletal beta troponin T cDNA: comparative sequence analysis of isoforms and insight into the evolution of members of a multigene family". DNA Cell Biol. 13 (3): 217–33. doi:10.1089/dna.1994.13.217. PMID   8172653.
  6. ↑ "Entrez Gene: TNNT3 troponin T type 3 (skeletal, fast)".
  7. 1 2 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 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. ↑ Wu QL, Jha PK, Raychowdhury MK, Du Y, Leavis PC, Sarkar S (Mar 1994). "Isolation and characterization of human fast skeletal beta troponin T cDNA: comparative sequence analysis of isoforms and insight into the evolution of members of a multigene family". DNA and Cell Biology. 13 (3): 217–33. doi:10.1089/dna.1994.13.217. PMID   8172653.
  11. ↑ 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.
  12. 1 2 Wilkinson JM, Moir AJ, Waterfield MD (Aug 1984). "The expression of multiple forms of troponin T in chicken-fast-skeletal muscle may result from differential splicing of a single gene". European Journal of Biochemistry. 143 (1): 47–56. doi: 10.1111/j.1432-1033.1984.tb08337.x . PMID   6468390.
  13. ↑ Breitbart RE, Nadal-Ginard B (Apr 1986). "Complete nucleotide sequence of the fast skeletal troponin T gene. Alternatively spliced exons exhibit unusual interspecies divergence". Journal of Molecular Biology. 188 (3): 313–24. doi:10.1016/0022-2836(86)90157-9. PMID   3735424.
  14. 1 2 3 Wang J, Jin JP (Jul 1997). "Primary structure and developmental acidic to basic transition of 13 alternatively spliced mouse fast skeletal muscle troponin T isoforms". Gene. 193 (1): 105–14. doi:10.1016/s0378-1119(97)00100-5. PMID   9249073.
  15. ↑ Medford RM, Nguyen HT, Destree AT, Summers E, Nadal-Ginard B (Sep 1984). "A novel mechanism of alternative RNA splicing for the developmentally regulated generation of troponin T isoforms from a single gene". Cell. 38 (2): 409–21. doi:10.1016/0092-8674(84)90496-3. PMID   6205765. S2CID   13476798.
  16. ↑ Smillie LB, Golosinska K, Reinach FC (Dec 1988). "Sequences of complete cDNAs encoding four variants of chicken skeletal muscle troponin T". The Journal of Biological Chemistry. 263 (35): 18816–20. doi: 10.1016/S0021-9258(18)37355-1 . PMID   3198600.
  17. ↑ Miyazaki J, Jozaki M, Nakatani N, Watanabe T, Saba R, Nakada K, Hirabayashi T, Yonemura I (Oct 1999). "The structure of the avian fast skeletal muscle troponin T gene: seven novel tandem-arranged exons in the exon x region". Journal of Muscle Research and Cell Motility. 20 (7): 655–60. doi:10.1023/A:1005504018059. PMID   10672513. S2CID   27513819.
  18. ↑ Jin JP, Samanez RA (Feb 2001). "Evolution of a metal-binding cluster in the NH(2)-terminal variable region of avian fast skeletal muscle troponin T: functional divergence on the basis of tolerance to structural drifting". Journal of Molecular Evolution. 52 (2): 103–16. Bibcode:2001JMolE..52..103J. doi:10.1007/s002390010139. PMID   11231890. S2CID   21386486.
  19. ↑ Imai H, Hirai S, Hirono H, Hirabayashi T (Mar 1986). "Many isoforms of fast muscle troponin T from chicken legs". Journal of Biochemistry. 99 (3): 923–30. doi:10.1093/oxfordjournals.jbchem.a135554. PMID   3711049.
  20. 1 2 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.
  21. ↑ Wang J, Jin JP (Oct 1998). "Conformational modulation of troponin T by configuration of the NH2-terminal variable region and functional effects". Biochemistry. 37 (41): 14519–28. doi:10.1021/bi9812322. PMID   9772180.
  22. ↑ Biesiadecki BJ, Chong SM, Nosek TM, Jin JP (Feb 2007). "Troponin T core structure and the regulatory NH2-terminal variable region". Biochemistry. 46 (5): 1368–79. doi:10.1021/bi061949m. PMC   1794682 . PMID   17260966.
  23. ↑ 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.
  24. 1 2 Ogut O, Jin JP (Oct 1998). "Developmentally regulated, alternative RNA splicing-generated pectoral muscle-specific troponin T isoforms and role of the NH2-terminal hypervariable region in the tolerance to acidosis". The Journal of Biological Chemistry. 273 (43): 27858–66. doi: 10.1074/jbc.273.43.27858 . PMID   9774396.
  25. ↑ 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.
  26. ↑ Wu QL, Jha PK, Du Y, Leavis PC, Sarkar S (Apr 1995). "Overproduction and rapid purification of human fast skeletal beta troponin T using Escherichia coli expression vectors: functional differences between the alpha and beta isoforms". Gene. 155 (2): 225–30. doi:10.1016/0378-1119(94)00846-K. PMID   7721095.
  27. 1 2 3 Jin JP, Smillie LB (Mar 1994). "An unusual metal-binding cluster found exclusively in the avian breast muscle troponin T of Galliformes and Craciformes". FEBS Letters. 341 (1): 135–40. Bibcode:1994FEBSL.341..135J. doi: 10.1016/0014-5793(94)80256-4 . PMID   8137914. S2CID   35786499.
  28. ↑ Zhang Z, Jin JP, Root DD (Mar 2004). "Binding of calcium ions to an avian flight muscle troponin T". Biochemistry. 43 (9): 2645–55. doi:10.1021/bi035067o. PMID   14992602.
  29. ↑ Ogut O, Granzier H, Jin JP (May 1999). "Acidic and basic troponin T isoforms in mature fast-twitch skeletal muscle and effect on contractility". The American Journal of Physiology. 276 (5 Pt 1): C1162–70. doi:10.1152/ajpcell.1999.276.5.C1162. PMID   10329966.
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