TNNI1 explained

Troponin I, slow skeletal muscle is a protein that in humans is encoded by the TNNI1 gene.^{[1] [2] [3]} It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

Gene TNNI1, troponin I type 1 (skeletal muscle, slow), also known as TNN1 and SSTNI, is located at 1q31.3 in the human chromosomal genome, encoding the slow twitch skeletal muscle isoform of troponin I (ssTnI), the inhibitory subunit of the troponin complex in striated muscle myofilaments.^{[4] [5]} Human TNNI1 spans 12.5 kilobases in the genomic DNA and contains 9 exons and 8 introns.^[2] Exon 2 to exon 8 contain the coding sequences, encoding a protein of 21.7 kDa consisting of 187 amino acids including the first methionine with an isoelectric point (pI) of 9.59.

Gene evolution

Three homologous genes have evolved in vertebrates, encoding three muscle type-specific isoforms of TnI.^{[6] [7]} In mammals, the amino acid sequence of ssTnI is highly conserved. Mouse and bovine ssTnI each differs from human ssTnI in only four amino acids, and rhesus monkey ssTnI is identical to human in the amino acid sequences. In lower vertebrates, the divergence of ssTnI between species is larger than that in the higher vertebrates (Fig1).

Tissue distribution

Comparing with the fast twitch skeletal muscle and cardiac TnI isoform genes (TNNT2 and TNNT3), TNNI1 has a broader range of expression in avian and mammalian striated muscles. It is the predominant TnI isoform expressed in both slow skeletal muscle and cardiac muscle in early embryonic stage.^[8] An isoform switch from ssTnI to cTnI occurs during perinatal heart development.^{[9] [10]} ssTnI is not expressed in the embryonic hearts of Xenopus and zebrafish, while it is expressed in the somites and skeletal muscles.^{[11] [12]}

Structure-function relationships

The function of TnI is to control striated muscle contraction and relaxation. Troponin I interacts with all major regulatory proteins in the sarcomeric thin filaments of cardiac and skeletal muscles: troponin C, troponin T, tropomyosin and actin. When cytosolic Ca²⁺ is low, TnI binds the thin filament to block the myosin binding sites on actin. The rise of cytosolic Ca²⁺ results in binding to the N-terminal domain of troponin C and induces conformational changes in troponin C and the troponin complex, which releases the inhibition of myosin-actin interaction and activates myosin ATPase and cross bridge cycling to generate myosin power strokes and muscle contraction.

To date, no high resolution structure of ssTnI has been solved. As homologous proteins, ssTnI, fast skeletal muscle TnI and cardiac TnI have highly conserved structures and crystallographic high resolution structure of partial cardiac and fast skeletal troponin complex are both available. Therefore, the structure-function relationship of ssTnI would rely on the information from studies performed on fast skeletal muscle and cardiac TnI.

Posttranslational modifications

To date, no posttranslational modification of ssTnI has been identified.

Mutations

To date, no human disease has been reported with mutations in TNNI1.

Clinical significance

Slow to fast skeletal TnI isoform switch occurs as an indicator for slow to fast fiber type transition in muscle adaptations.^[13] Slow skeletal TnI has been proposed as a sensitive and muscle fiber type-specific marker for skeletal muscle injuries.^{[14] [15]} In patients with skeletal muscle disorders, intact ssTnI or its degraded products may be detected in peripheral blood as a diagnostic indicator for slow fiber damages.

Further reading

• Hunkeler NM, Kullman J, Murphy AM . Troponin I isoform expression in human heart . Circulation Research . 69 . 5 . 1409–14 . Nov 1991 . 1934363 . 10.1161/01.res.69.5.1409 . free .
• Bhavsar PK, Dhoot GK, Cumming DV, Butler-Browne GS, Yacoub MH, Barton PJ . Developmental expression of troponin I isoforms in fetal human heart . FEBS Letters . 292 . 1–2 . 5–8 . Nov 1991 . 1959627 . 10.1016/0014-5793(91)80820-S . free .
• Suzuki H, Kawarabayasi Y, Kondo J, Abe T, Nishikawa K, Kimura S, Hashimoto T, Yamamoto T . Structure and regulation of rat long-chain acyl-CoA synthetase . The Journal of Biological Chemistry . 265 . 15 . 8681–5 . May 1990 . 10.1016/S0021-9258(19)38942-2 . 2341402 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Jha PK, Leavis PC, Sarkar S . Interaction of deletion mutants of troponins I and T: COOH-terminal truncation of troponin T abolishes troponin I binding and reduces Ca2+ sensitivity of the reconstituted regulatory system . Biochemistry . 35 . 51 . 16573–80 . Dec 1996 . 8987992 . 10.1021/bi9622433 .
• Tiso N, Rampoldi L, Pallavicini A, Zimbello R, Pandolfo D, Valle G, Lanfranchi G, Danieli GA . Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast . Biochemical and Biophysical Research Communications . 230 . 2 . 347–50 . Jan 1997 . 9016781 . 10.1006/bbrc.1996.5958 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Jha PK, Sarkar S . A recombinant monocysteine mutant (Ser to Cys-155) of fast skeletal troponin T: identification by cross-linking of a domain involved in a physiologically relevant interaction with troponins C and I . Biochemistry . 37 . 35 . 12253–60 . Sep 1998 . 9724539 . 10.1021/bi980025z .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . Nov 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A . Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs . Genome Research . 11 . 3 . 422–35 . Mar 2001 . 11230166 . 311072 . 10.1101/gr.GR1547R .
• Lindhout DA, Li MX, Schieve D, Sykes BD . Effects of T142 phosphorylation and mutation R145G on the interaction of the inhibitory region of human cardiac troponin I with the C-domain of human cardiac troponin C . Biochemistry . 41 . 23 . 7267–74 . Jun 2002 . 12044157 . 10.1021/bi020100c .
• Westfall MV, Borton AR . Role of troponin I phosphorylation in protein kinase C-mediated enhanced contractile performance of rat myocytes . The Journal of Biological Chemistry . 278 . 36 . 33694–700 . Sep 2003 . 12815045 . 10.1074/jbc.M305404200 . free .
• Polly P, Haddadi LM, Issa LL, Subramaniam N, Palmer SJ, Tay ES, Hardeman EC . hMusTRD1alpha1 represses MEF2 activation of the troponin I slow enhancer . The Journal of Biological Chemistry . 278 . 38 . 36603–10 . Sep 2003 . 12857748 . 10.1074/jbc.M212814200 . free .
• Thijssen VL, Ausma J, Gorza L, van der Velden HM, Allessie MA, Van Gelder IC, Borgers M, van Eys GJ . Troponin I isoform expression in human and experimental atrial fibrillation . Circulation . 110 . 7 . 770–5 . Aug 2004 . 15289369 . 10.1161/01.CIR.0000138849.03311.C6 . 975263 .
• Brobbey A, Ravakhah K . Elevated serum cardiac troponin I level in a patient after a grand mal seizure and with no evidence of cardiac disease . The American Journal of the Medical Sciences . 328 . 3 . 189–91 . Sep 2004 . 15367881 . 10.1097/00000441-200409000-00012 . 43056822 .

Notes and References

1. Wade R, Eddy R, Shows TB, Kedes L . cDNA sequence, tissue-specific expression, and chromosomal mapping of the human slow-twitch skeletal muscle isoform of troponin I . Genomics . 7 . 3 . 346–57 . Jul 1990 . 2365354 . 10.1016/0888-7543(90)90168-T .
2. Corin SJ, Juhasz O, Zhu L, Conley P, Kedes L, Wade R . Structure and expression of the human slow twitch skeletal muscle troponin I gene . The Journal of Biological Chemistry . 269 . 14 . 10651–9 . Apr 1994 . 10.1016/S0021-9258(17)34109-1 . 8144655 . free .
3. Web site: Entrez Gene: TNNI1 troponin I type 1 (skeletal, slow).
4. Perry SV . Troponin I: inhibitor or facilitator . Molecular and Cellular Biochemistry . 190 . 1–2 . 9–32 . Jan 1999 . 10098965 . 10.1023/A:1006939307715 . 23721684 .
5. Jin JP, Zhang Z, Bautista JA . Isoform diversity, regulation, and functional adaptation of troponin and calponin . Critical Reviews in Eukaryotic Gene Expression . 18 . 2 . 93–124 . 18304026 . 10.1615/critreveukargeneexpr.v18.i2.10 . 2008.
6. Hastings KE . Molecular evolution of the vertebrate troponin I gene family . Cell Structure and Function . 22 . 1 . 205–11 . Feb 1997 . 9113408 . 10.1247/csf.22.205 . free .
7. Chong SM, Jin JP . To investigate protein evolution by detecting suppressed epitope structures . Journal of Molecular Evolution . 68 . 5 . 448–60 . May 2009 . 19365646 . 10.1007/s00239-009-9202-0 . 2752406. 2009JMolE..68..448C .
8. Sasse S, Brand NJ, Kyprianou P, Dhoot GK, Wade R, Arai M, Periasamy M, Yacoub MH, Barton PJ . Troponin I gene expression during human cardiac development and in end-stage heart failure . Circulation Research . 72 . 5 . 932–8 . May 1993 . 8477526 . 10.1161/01.res.72.5.932. free .
9. Saggin L, Gorza L, Ausoni S, Schiaffino S . Troponin I switching in the developing heart . The Journal of Biological Chemistry . 264 . 27 . 16299–302 . Sep 1989 . 10.1016/S0021-9258(18)71621-9 . 2777792 . free .
10. Jin JP . Alternative RNA splicing-generated cardiac troponin T isoform switching: a non-heart-restricted genetic programming synchronized in developing cardiac and skeletal muscles . Biochemical and Biophysical Research Communications . 225 . 3 . 883–9 . Aug 1996 . 8780706 . 10.1006/bbrc.1996.1267 .
11. Warkman AS, Atkinson BG . The slow isoform of Xenopus troponin I is expressed in developing skeletal muscle but not in the heart . Mechanisms of Development . 115 . 1–2 . 143–6 . Jul 2002 . 12049779 . 10.1016/s0925-4773(02)00096-5. 12461520 .
12. Fu CY, Lee HC, Tsai HJ . The molecular structures and expression patterns of zebrafish troponin I genes . Gene Expression Patterns . 9 . 5 . 348–56 . Jun 2009 . 19602390 . 10.1016/j.gep.2009.02.001 .
13. Stevens L, Bastide B, Kischel P, Pette D, Mounier Y . Time-dependent changes in expression of troponin subunit isoforms in unloaded rat soleus muscle . American Journal of Physiology. Cell Physiology . 282 . 5 . C1025–30 . May 2002 . 11940518 . 10.1152/ajpcell.00252.2001 . 11767406 .
14. Simpson JA, Labugger R, Collier C, Brison RJ, Iscoe S, Van Eyk JE . Fast and slow skeletal troponin I in serum from patients with various skeletal muscle disorders: a pilot study . Clinical Chemistry . 51 . 6 . 966–72 . Jun 2005 . 15833785 . 10.1373/clinchem.2004.042671 . free .
15. Chapman DW, Simpson JA, Iscoe S, Robins T, Nosaka K . Changes in serum fast and slow skeletal troponin I concentration following maximal eccentric contractions . Journal of Science and Medicine in Sport . 16 . 1 . 82–5 . Jan 2013 . 22795680 . 10.1016/j.jsams.2012.05.006 . free .