Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3gene.[5][6]
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.[7][8]
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.[8]
Tissue distribution
TNNI3 is expressed as a heart specific gene.[8] 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.[9] cTnI completely replaces slow TnI in the mouse heart approximately 14 days after birth [10]
Protein structure
Based on in vitro
structure-function relationship studies, the structure of cTnI can be divided into six functional segments:[11]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.[12]
Posttranslational modifications
Phosphorylation: cTnI was the first sarcomeric protein identified to be a substrate of PKA.[13] 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.[14] Ser5/Ser6, Tyr26, Thr31, Ser39, Thr51, Ser77, Thr78, Thr129, Thr143 and Ser150 are also phosphorylation sites in human cTnI.[15]
O-linked GlcNAc modification: Studies on isolated cardiomyocytes found increased levels of O-GlcNAcylation of cardiac proteins in hearts with diabetic dysfunction.[16] Mass spectrometry identified Ser150 of mouse cTnI as an O-GlcNAcylation site, suggesting a potential role in regulating myocardial contractility.
C-terminal truncation: The C-terminal end segment is the most conserved region of TnI.[17] As an allosteric structure regulated by Ca2+ in the troponin complex,[17][18][19] it binds and stabilizes the position of tropomyosin in low Ca2+ state[18][20] 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.[21] It was also seen in myocardial stunning in coronary bypass patients.[22] 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.[23] 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.[24]
Restrictive N-terminal truncation: The approximately 30 amino acids N-terminal extension of cTnI is an adult heart-specific structure.[25][26] 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.[27] 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[28] and Gsα deficiency-caused failing mouse hearts.[29] 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.[30]
Pathologic mutations
Multiple mutations in cTnI have been found to cause cardiomyopathies.[31][32] cTnI mutations account for approximately 5% of familial hypertrophic cardiomyopathy cases and to date, more than 20 myopathic mutations of cTnI have been characterized.[15]
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.[33] 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.[34] An increased level of serum cTnI also independently predicts poor prognosis of critically ill patients in the absence of acute coronary syndrome.[35][36]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. PMID9605869.
^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. PMID9241277. S2CID31578767.
^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. PMID15711886. S2CID8973787.
^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. PMID17135297. S2CID7165718.
^ abJin 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. PMID11327886.
^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. PMID22455086.
^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. PMID25534985.
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. PMID11596911.
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. PMID1959915. S2CID5850640.
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. PMID8125298.
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. PMID8406024.
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. PMID8661099.
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. PMID9373149.
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. PMID10191089.
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. PMID10387074.
