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Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3 gene.[1][2] It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

The TNNI3 gene encoding cardiac troponin I (cTnI) is located at 19q13.4 in the human chromosomal genome. Human cTnI is a 24 kDa protein consisting of 210 amino acids with isoelectric point (pI) of 9.87. cTnI is exclusively expressed in adult cardiac muscle.[3][4]

Gene evolution

File:7-27 cTnI align.jpg
Figure 1: A phylogenetic tree is derived from alignment of amino acid sequences.

cTnI has diverged from the skeletal muscle isoforms of TnI (slow TnI and fast TnI) mainly with a unique N-terminal extension. The amino acid sequence of cTnI is strongly conserved among mammalian species (Fig. 1). On the other hand, the N-terminal extension of cTnI has significantly different structures among mammal, amphibian and fish.[4]

Tissue distribution

TNNI3 is expressed as a heart specific gene.[4] Early embryonic heart expresses solely slow skeletal muscle TnI. cTnI begins to express in mouse heart at approximately embryonic day 10, and the level gradually increases to one-half of the total amount of TnI in the cardiac muscle at birth.[5] cTnI completely replaces slow TnI in the mouse heart approximately 14 days after birth [6]

Protein structure

Based on in vitro structure-function relationship studies, the structure of cTnI can be divided into six functional segments:[7] a) a cardiac-specific N-terminal extension (residue 1–30) that is not present in fast TnI and slow TnI; b) an N-terminal region (residue 42–79) that binds the C domain of TnC; c) a TnT-binding region (residue 80–136); d) the inhibitory peptide (residue 128–147) that interacts with TnC and actin–tropomyosin; e) the switch or triggering region (residue 148–163) that binds the N domain of TnC; and f) the C-terminal mobile domain (residue 164–210) that binds actin–tropomyosin and is the most conserved segment highly similar among isoforms and across species. Partially crystal structure of human troponin has been determined.[8]

Posttranslational modifications

  1. Phosphorylation: cTnI was the first sarcomeric protein identified to be a substrate of PKA.[9] Phosphorylation of cTnI at Ser23/Ser24 under adrenergic stimulation enhances relaxation of cardiac muscle, which is critical to cardiac function especially at fast heart rate. Whereas PKA phosphorylation of Ser23/Ser24 decreases myofilament Ca2+ sensitivity and increases relaxation, phosphorylation of Ser42/Ser44 by PKC increases Ca2+ sensitivity and decreases cardiac muscle relaxation.[10] Ser5/Ser6, Tyr26, Thr31, Ser39, Thr51, Ser77, Thr78, Thr129, Thr143 and Ser150 are also phosphorylation sites in human cTnI.[11]
  2. O-linked GlcNAc modification: Studies on isolated cardiomyocytes found increased levels of O-GlcNAcylation of cardiac proteins in hearts with diabetic dysfunction.[12] Mass spectrometry identified Ser150 of mouse cTnI as an O-GlcNAcylation site, suggesting a potential role in regulating myocardial contractility.
  3. C-terminal truncation: The C-terminal end segment is the most conserved region of TnI.[13] As an allosteric structure regulated by Ca2+ in the troponin complex,[13][14][15] it binds and stabilizes the position of tropomyosin in low Ca2+ state[14][16] implicating a role in the inhibition of actomyosin ATPase. A deletion of the C-terminal 19 amino acids was found during myocardial ischemia-reperfusion injury in Langendorff perfused rat hearts.[17] It was also seen in myocardial stunning in coronary bypass patients.[18] Over-expression of the C-terminal truncated cardiac TnI (cTnI1-192) in transgenic mouse heart resulted in a phenotype of myocardial stunning with systolic and diastolic dysfunctions.[19] Replacement of intact cTnI with cTnT1-192 in myofibrils and cardiomyocytes did not affect maximal tension development but decreased the rates of force redevelopment and relaxation.[20]
  4. Restrictive N-terminal truncation: The approximately 30 amino acids N-terminal extension of cTnI is an adult heart-specific structure.[21][22] The N-terminal extension contains the PKA phosphorylation sites Ser23/Ser24 and plays a role in modulating the overall molecular conformation and function of cTnI.[23] A restrictive N-terminal truncation of cTnI occurs at low levels in normal hearts of all vertebrate species examined including human and significantly increases in adaptation to hemodynamic stress[24] and Gsα deficiency-caused failing mouse hearts.[25] Distinct from the harmful C-terminal truncation, the restrictive N-terminal truncation of cTnI selectively removing the adult heart specific extension forms a regulatory mechanism in cardiac adaptation to physiological and pathological stress conditions.[26]

Pathologic mutations

Multiple mutations in cTnI have been found to cause cardiomyopathies.[27][28] cTnI mutations account for approximately 5% of familial hypertrophic cardiomyopathy cases and to date, more than 20 myopathic mutations of cTnI have been characterized.[11]

Clinical implications

The half-life of cTnI in adult cardiomyocytes is estimated to be ~3.2 days and there is a pool of unassembled cardiac TnI in the cytoplasm.[29] Cardiac TnI is exclusively expressed in the myocardium and is thus a highly specific diagnostic marker for cardiac muscle injuries, and cTnI has been universally used as indicator for myocardial infarction.[30] An increased level of serum cTnI also independently predicts poor prognosis of critically ill patients in the absence of acute coronary syndrome.[31][32]



  1. Mogensen J, Kruse TA, Børglum AD (Jun 1998). "Assignment of the human cardiac troponin I gene (TNNI3) to chromosome 19q13.4 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 79 (3–4): 272–3. doi:10.1159/000134740. PMID 9605869.
  2. Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang TH, Choo JA, Chung KS, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki M, Sakamoto T, Toshima H, Koga Y, Imaizumi T, Sasazuki T (Aug 1997). "Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy". Nature Genetics. 16 (4): 379–82. doi:10.1038/ng0897-379. PMID 9241277.
  3. Bodor GS, Porterfield D, Voss EM, Smith S, Apple FS (Dec 1995). "Cardiac troponin-I is not expressed in fetal and healthy or diseased adult human skeletal muscle tissue". Clinical Chemistry. 41 (12 Pt 1): 1710–5. PMID 7497610.
  4. 4.0 4.1 4.2 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.
  5. Jin JP (Aug 1996). "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. doi:10.1006/bbrc.1996.1267. PMID 8780706.
  6. Feng HZ, Hossain MM, Huang XP, Jin JP (Jul 2009). "Myofilament incorporation determines the stoichiometry of troponin I in transgenic expression and the rescue of a null mutation". Archives of Biochemistry and Biophysics. 487 (1): 36–41. doi:10.1016/ PMC 2752407. PMID 19433057.
  7. Li MX, Wang X, Sykes BD (2004-01-01). "Structural based insights into the role of troponin in cardiac muscle pathophysiology". Journal of Muscle Research and Cell Motility. 25 (7): 559–79. doi:10.1007/s10974-004-5879-2. PMID 15711886.
  8. PDB: 1J1E 1J1E​; Takeda S, Yamashita A, Maeda K, Maéda Y (Jul 2003). "Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form". Nature. 424 (6944): 35–41. doi:10.1038/nature01780. PMID 12840750.
  9. Stull JT, Brostrom CO, Krebs EG (Aug 1972). "Phosphorylation of the inhibitor component of troponin by phosphorylase kinase". The Journal of Biological Chemistry. 247 (16): 5272–4. PMID 4262569.
  10. Solaro RJ, van der Velden J (May 2010). "Why does troponin I have so many phosphorylation sites? Fact and fancy". Journal of Molecular and Cellular Cardiology. 48 (5): 810–6. doi:10.1016/j.yjmcc.2010.02.014. PMC 2854207. PMID 20188739.
  11. 11.0 11.1 Sheng JJ, Jin JP (2014-01-01). "Gene regulation, alternative splicing, and posttranslational modification of troponin subunits in cardiac development and adaptation: a focused review". Frontiers in Physiology. 5: 165. doi:10.3389/fphys.2014.00165. PMC 4012202. PMID 24817852.
  12. Fülöp N, Mason MM, Dutta K, Wang P, Davidoff AJ, Marchase RB, Chatham JC (Apr 2007). "Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart". American Journal of Physiology. Cell Physiology. 292 (4): C1370–8. doi:10.1152/ajpcell.00422.2006. PMID 17135297.
  13. 13.0 13.1 Jin JP, Yang FW, Yu ZB, Ruse CI, Bond M, Chen A (Feb 2001). "The highly conserved COOH terminus of troponin I forms a Ca2+-modulated allosteric domain in the troponin complex". Biochemistry. 40 (8): 2623–31. doi:10.1021/bi002423j. PMID 11327886.
  14. 14.0 14.1 Zhang Z, Akhter S, Mottl S, Jin JP (Sep 2011). "Calcium-regulated conformational change in the C-terminal end segment of troponin I and its binding to tropomyosin". The FEBS Journal. 278 (18): 3348–59. doi:10.1111/j.1742-4658.2011.08250.x. PMC 3168705. PMID 21777381.
  15. Wang H, Chalovich JM, Marriott G (2012-01-01). "Structural dynamics of troponin I during Ca2+-activation of cardiac thin filaments: a multi-site Förster resonance energy transfer study". PLOS ONE. 7 (12): e50420. doi:10.1371/journal.pone.0050420. PMC 3515578. PMID 23227172.
  16. Galińska A, Hatch V, Craig R, Murphy AM, Van Eyk JE, Wang CL, Lehman W, Foster DB (Mar 2010). "The C terminus of cardiac troponin I stabilizes the Ca2+-activated state of tropomyosin on actin filaments". Circulation Research. 106 (4): 705–11. doi:10.1161/CIRCRESAHA.109.210047. PMC 2834238. PMID 20035081.,
  17. McDonough JL, Arrell DK, Van Eyk JE (1999-01-08). "Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury". Circulation Research. 84 (1): 9–20. doi:10.1161/01.res.84.1.9. PMID 9915770.
  18. McDonough JL, Labugger R, Pickett W, Tse MY, MacKenzie S, Pang SC, Atar D, Ropchan G, Van Eyk JE (Jan 2001). "Cardiac troponin I is modified in the myocardium of bypass patients". Circulation. 103 (1): 58–64. doi:10.1161/01.cir.103.1.58. PMID 11136686.
  19. Murphy AM, Kögler H, Georgakopoulos D, McDonough JL, Kass DA, Van Eyk JE, Marbán E (Jan 2000). "Transgenic mouse model of stunned myocardium". Science. 287 (5452): 488–91. doi:10.1126/science.287.5452.488. PMID 10642551.
  20. Narolska NA, Piroddi N, Belus A, Boontje NM, Scellini B, Deppermann S, Zaremba R, Musters RJ, dos Remedios C, Jaquet K, Foster DB, Murphy AM, van Eyk JE, Tesi C, Poggesi C, van der Velden J, Stienen GJ (Oct 2006). "Impaired diastolic function after exchange of endogenous troponin I with C-terminal truncated troponin I in human cardiac muscle". Circulation Research. 99 (9): 1012–20. doi:10.1161/ PMID 17023673.
  21. Perry SV (Jan 1999). "Troponin I: inhibitor or facilitator". Molecular and Cellular Biochemistry. 190 (1–2): 9–32. doi:10.1023/A:1006939307715. PMID 10098965.
  22. Chong SM, Jin JP (May 2009). "To investigate protein evolution by detecting suppressed epitope structures". Journal of Molecular Evolution. 68 (5): 448–60. doi:10.1007/s00239-009-9202-0. PMC 2752406. PMID 19365646.
  23. Akhter S, Zhang Z, Jin JP (Feb 2012). "The heart-specific NH2-terminal extension regulates the molecular conformation and function of cardiac troponin I". American Journal of Physiology. Heart and Circulatory Physiology. 302 (4): H923–33. doi:10.1152/ajpheart.00637.2011. PMC 3322736. PMID 22140044.
  24. Yu ZB, Zhang LF, Jin JP (May 2001). "A proteolytic NH2-terminal truncation of cardiac troponin I that is up-regulated in simulated microgravity". The Journal of Biological Chemistry. 276 (19): 15753–60. doi:10.1074/jbc.M011048200. PMID 11278823.
  25. Barbato JC, Huang QQ, Hossain MM, Bond M, Jin JP (Feb 2005). "Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function". The Journal of Biological Chemistry. 280 (8): 6602–9. doi:10.1074/jbc.M408525200. PMID 15611140.
  26. Feng HZ, Chen M, Weinstein LS, Jin JP (Nov 2008). "Removal of the N-terminal extension of cardiac troponin I as a functional compensation for impaired myocardial beta-adrenergic signaling". The Journal of Biological Chemistry. 283 (48): 33384–93. doi:10.1074/jbc.M803302200. PMC 2586242. PMID 18815135.
  27. Seidman JG, Seidman C (Feb 2001). "The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms". Cell. 104 (4): 557–67. doi:10.1016/s0092-8674(01)00242-2. PMID 11239412.
  28. Curila K, Benesova L, Penicka M, Minarik M, Zemanek D, Veselka J, Widimsky P, Gregor P (Feb 2012). "Spectrum and clinical manifestations of mutations in genes responsible for hypertrophic cardiomyopathy". Acta Cardiologica. 67 (1): 23–9. doi:10.2143/AC.67.1.2146562. PMID 22455086.
  29. 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. PMID 7451483.
  30. Januzzi JL, Filippatos G, Nieminen M, Gheorghiade M (Sep 2012). "Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section". European Heart Journal. 33 (18): 2265–71. doi:10.1093/eurheartj/ehs191. PMID 22745356.
  31. Reynolds T, Cecconi M, Collinson P, Rhodes A, Grounds RM, Hamilton MA (Aug 2012). "Raised serum cardiac troponin I concentrations predict hospital mortality in intensive care unit patients". British Journal of Anaesthesia. 109 (2): 219–24. doi:10.1093/bja/aes141. PMID 22617093.
  32. Lee YJ, Lee H, Park JS, Kim SJ, Cho YJ, Yoon HI, Lee JH, Lee CT, Park JS (Apr 2015). "Cardiac troponin I as a prognostic factor in critically ill pneumonia patients in the absence of acute coronary syndrome". Journal of Critical Care. 30 (2): 390–4. doi:10.1016/j.jcrc.2014.12.001. PMID 25534985.

Further reading

  • Ni CY (2002). "Cardiac troponin I: a biomarker for detection and risk stratification of minor myocardial damage". Clinical Laboratory. 47 (9–10): 483–92. PMID 11596911.
  • Hunkeler NM, Kullman J, Murphy AM (Nov 1991). "Troponin I isoform expression in human heart". Circulation Research. 69 (5): 1409–14. doi:10.1161/01.res.69.5.1409. PMID 1934363.
  • MacGeoch C, Barton PJ, Vallins WJ, Bhavsar P, Spurr NK (Nov 1991). "The human cardiac troponin I locus: assignment to chromosome 19p13.2-19q13.2". Human Genetics. 88 (1): 101–4. doi:10.1007/BF00204938. PMID 1959915.
  • Vallins WJ, Brand NJ, Dabhade N, Butler-Browne G, Yacoub MH, Barton PJ (Sep 1990). "Molecular cloning of human cardiac troponin I using polymerase chain reaction". FEBS Letters. 270 (1–2): 57–61. doi:10.1016/0014-5793(90)81234-F. PMID 2226790.
  • Mittmann K, Jaquet K, Heilmeyer LM (Oct 1990). "A common motif of two adjacent phosphoserines in bovine, rabbit and human cardiac troponin I". FEBS Letters. 273 (1–2): 41–5. doi:10.1016/0014-5793(90)81046-Q. PMID 2226863.
  • Noland TA, Raynor RL, Kuo JF (Dec 1989). "Identification of sites phosphorylated in bovine cardiac troponin I and troponin T by protein kinase C and comparative substrate activity of synthetic peptides containing the phosphorylation sites". The Journal of Biological Chemistry. 264 (34): 20778–85. PMID 2584239.
  • Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
  • Armour KL, Harris WJ, Tempest PR (Sep 1993). "Cloning and expression in Escherichia coli of the cDNA encoding human cardiac troponin I". Gene. 131 (2): 287–92. doi:10.1016/0378-1119(93)90308-P. PMID 8406024.
  • Bhavsar PK, Brand NJ, Yacoub MH, Barton PJ (Jul 1996). "Isolation and characterization of the human cardiac troponin I gene (TNNI3)". Genomics. 35 (1): 11–23. doi:10.1006/geno.1996.0317. PMID 8661099.
  • Jideama NM, Noland TA, Raynor RL, Blobe GC, Fabbro D, Kazanietz MG, Blumberg PM, Hannun YA, Kuo JF (Sep 1996). "Phosphorylation specificities of protein kinase C isozymes for bovine cardiac troponin I and troponin T and sites within these proteins and regulation of myofilament properties". The Journal of Biological Chemistry. 271 (38): 23277–83. doi:10.1074/jbc.271.38.23277. PMID 8798526.
  • Takeda S, Kobayashi T, Taniguchi H, Hayashi H, Maéda Y (Jun 1997). "Structural and functional domains of the troponin complex revealed by limited digestion". European Journal of Biochemistry / FEBS. 246 (3): 611–7. doi:10.1111/j.1432-1033.1997.00611.x. PMID 9219516.
  • Keane NE, Quirk PG, Gao Y, Patchell VB, Perry SV, Levine BA (Sep 1997). "The ordered phosphorylation of cardiac troponin I by the cAMP-dependent protein kinase--structural consequences and functional implications". European Journal of Biochemistry / FEBS. 248 (2): 329–37. doi:10.1111/j.1432-1033.1997.00329.x. PMID 9346285.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
  • Vassylyev DG, Takeda S, Wakatsuki S, Maeda K, Maéda Y (Apr 1998). "Crystal structure of troponin C in complex with troponin I fragment at 2.3-A resolution". Proceedings of the National Academy of Sciences of the United States of America. 95 (9): 4847–52. doi:10.1073/pnas.95.9.4847. PMC 20176. PMID 9560191.
  • Barton PJ, Cullen ME, Townsend PJ, Brand NJ, Mullen AJ, Norman DA, Bhavsar PK, Yacoub MH (Apr 1999). "Close physical linkage of human troponin genes: organization, sequence, and expression of the locus encoding cardiac troponin I and slow skeletal troponin T". Genomics. 57 (1): 102–9. doi:10.1006/geno.1998.5702. PMID 10191089.
  • Li MX, Spyracopoulos L, Sykes BD (Jun 1999). "Binding of cardiac troponin-I147-163 induces a structural opening in human cardiac troponin-C". Biochemistry. 38 (26): 8289–98. doi:10.1021/bi9901679. PMID 10387074.
  • Redwood C, Lohmann K, Bing W, Esposito GM, Elliott K, Abdulrazzak H, Knott A, Purcell I, Marston S, Watkins H (Jun 2000). "Investigation of a truncated cardiac troponin T that causes familial hypertrophic cardiomyopathy: Ca(2+) regulatory properties of reconstituted thin filaments depend on the ratio of mutant to wild-type protein". Circulation Research. 86 (11): 1146–52. doi:10.1161/01.res.86.11.1146. PMID 10850966.
  • Ward DG, Ashton PR, Trayer HR, Trayer IP (Jan 2001). "Additional PKA phosphorylation sites in human cardiac troponin I". European Journal of Biochemistry / FEBS. 268 (1): 179–85. doi:10.1046/j.1432-1327.2001.01871.x. PMID 11121119.

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