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Biology:TNNI3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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

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]

Notes


References

  1. ↑ "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. Jun 1998. doi:10.1159/000134740. PMID 9605869. 
  2. ↑ "Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy". Nature Genetics 16 (4): 379–82. Aug 1997. doi:10.1038/ng0897-379. PMID 9241277. 
  3. ↑ "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. Dec 1995. doi:10.1093/clinchem/41.12.1710. PMID 7497610. http://www.clinchem.org/content/41/12/1710. 
  4. ↑ 4.0 4.1 4.2 "Isoform diversity, regulation, and functional adaptation of troponin and calponin". Critical Reviews in Eukaryotic Gene Expression 18 (2): 93–124. 2008. doi:10.1615/critreveukargeneexpr.v18.i2.10. PMID 18304026. 
  5. ↑ "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. doi:10.1006/bbrc.1996.1267. PMID 8780706. 
  6. ↑ "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. Jul 2009. doi:10.1016/j.abb.2009.05.001. PMID 19433057. 
  7. ↑ "Structural based insights into the role of troponin in cardiac muscle pathophysiology". Journal of Muscle Research and Cell Motility 25 (7): 559–79. 2004-01-01. doi:10.1007/s10974-004-5879-2. PMID 15711886. 
  8. ↑ PDB: 1J1E 1J1E​; "Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form". Nature 424 (6944): 35–41. Jul 2003. doi:10.1038/nature01780. PMID 12840750. Bibcode: 2003Natur.424...35T. 
  9. ↑ "Phosphorylation of the inhibitor component of troponin by phosphorylase kinase". The Journal of Biological Chemistry 247 (16): 5272–4. Aug 1972. doi:10.1016/S0021-9258(19)44967-3. PMID 4262569. 
  10. ↑ "Why does troponin I have so many phosphorylation sites? Fact and fancy". Journal of Molecular and Cellular Cardiology 48 (5): 810–6. May 2010. doi:10.1016/j.yjmcc.2010.02.014. PMID 20188739. 
  11. ↑ 11.0 11.1 "Gene regulation, alternative splicing, and posttranslational modification of troponin subunits in cardiac development and adaptation: a focused review". Frontiers in Physiology 5: 165. 2014-01-01. doi:10.3389/fphys.2014.00165. PMID 24817852. 
  12. ↑ "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. Apr 2007. doi:10.1152/ajpcell.00422.2006. PMID 17135297. 
  13. ↑ 13.0 13.1 "The highly conserved COOH terminus of troponin I forms a Ca2+-modulated allosteric domain in the troponin complex". Biochemistry 40 (8): 2623–31. Feb 2001. doi:10.1021/bi002423j. PMID 11327886. 
  14. ↑ 14.0 14.1 "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. Sep 2011. doi:10.1111/j.1742-4658.2011.08250.x. PMID 21777381. 
  15. ↑ "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. 2012-01-01. doi:10.1371/journal.pone.0050420. PMID 23227172. Bibcode: 2012PLoSO...750420W. 
  16. ↑ "The C terminus of cardiac troponin I stabilizes the Ca2+-activated state of tropomyosin on actin filaments". Circulation Research 106 (4): 705–11. Mar 2010. doi:10.1161/CIRCRESAHA.109.210047. PMID 20035081. ,
  17. ↑ "Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury". Circulation Research 84 (1): 9–20. 1999-01-08. doi:10.1161/01.res.84.1.9. PMID 9915770. 
  18. ↑ "Cardiac troponin I is modified in the myocardium of bypass patients". Circulation 103 (1): 58–64. Jan 2001. doi:10.1161/01.cir.103.1.58. PMID 11136686. 
  19. ↑ "Transgenic mouse model of stunned myocardium". Science 287 (5452): 488–91. Jan 2000. doi:10.1126/science.287.5452.488. PMID 10642551. Bibcode: 2000Sci...287..488M. 
  20. ↑ "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. Oct 2006. doi:10.1161/01.RES.0000248753.30340.af. PMID 17023673. 
  21. ↑ "Troponin I: inhibitor or facilitator". Molecular and Cellular Biochemistry 190 (1–2): 9–32. Jan 1999. doi:10.1023/A:1006939307715. PMID 10098965. 
  22. ↑ "To investigate protein evolution by detecting suppressed epitope structures". Journal of Molecular Evolution 68 (5): 448–60. May 2009. doi:10.1007/s00239-009-9202-0. PMID 19365646. Bibcode: 2009JMolE..68..448C. 
  23. ↑ "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. Feb 2012. doi:10.1152/ajpheart.00637.2011. PMID 22140044. 
  24. ↑ "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. May 2001. doi:10.1074/jbc.M011048200. PMID 11278823. 
  25. ↑ "Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function". The Journal of Biological Chemistry 280 (8): 6602–9. Feb 2005. doi:10.1074/jbc.M408525200. PMID 15611140. 
  26. ↑ "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. Nov 2008. doi:10.1074/jbc.M803302200. PMID 18815135. 
  27. ↑ "The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms". Cell 104 (4): 557–67. Feb 2001. doi:10.1016/s0092-8674(01)00242-2. PMID 11239412. 
  28. ↑ "Spectrum and clinical manifestations of mutations in genes responsible for hypertrophic cardiomyopathy". Acta Cardiologica 67 (1): 23–9. Feb 2012. doi:10.2143/AC.67.1.2146562. PMID 22455086. 
  29. ↑ "Turnover of cardiac troponin subunits. Kinetic evidence for a precursor pool of troponin-I". The Journal of Biological Chemistry 256 (2): 964–8. Jan 1981. doi:10.1016/S0021-9258(19)70073-8. PMID 7451483. 
  30. ↑ "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. Sep 2012. doi:10.1093/eurheartj/ehs191. PMID 22745356. 
  31. ↑ "Raised serum cardiac troponin I concentrations predict hospital mortality in intensive care unit patients". British Journal of Anaesthesia 109 (2): 219–24. Aug 2012. doi:10.1093/bja/aes141. PMID 22617093. 
  32. ↑ "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. Apr 2015. doi:10.1016/j.jcrc.2014.12.001. PMID 25534985. 

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