1. Gene evolution

2. Tissue distribution

3. Protein structure
     Posttranslational modifications  

4. Pathologic mutations

5. Clinical implications

6. Notes

7. References

8. Further reading

9. External links

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

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

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.^&91;9&93; 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.^&91;10&93; Ser₅/Ser₆, Tyr₂₆, Thr₃₁, Ser₃₉, Thr₅₁, Ser₇₇, Thr₇₈, Thr₁₂₉, Thr₁₄₃ and Ser₁₅₀ are also phosphorylation sites in human cTnI.^&91;11&93;
2. O-linked GlcNAc modification: Studies on isolated cardiomyocytes found increased levels of O-GlcNAcylation of cardiac proteins in hearts with diabetic dysfunction.^&91;12&93; 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.^&91;13&93; As an allosteric structure regulated by Ca²⁺ in the troponin complex,^{&91;13&93;&91;14&93;&91;15&93;} it binds and stabilizes the position of tropomyosin in low Ca²⁺ state^{&91;14&93;&91;16&93;} 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.^&91;17&93; It was also seen in myocardial stunning in coronary bypass patients.^&91;18&93; Over-expression of the C-terminal truncated cardiac TnI (cTnI_1-192) in transgenic mouse heart resulted in a phenotype of myocardial stunning with systolic and diastolic dysfunctions.^&91;19&93; Replacement of intact cTnI with cTnT_1-192 in myofibrils and cardiomyocytes did not affect maximal tension development but decreased the rates of force redevelopment and relaxation.^&91;20&93;
4. Restrictive N-terminal truncation: The approximately 30 amino acids N-terminal extension of cTnI is an adult heart-specific structure.^{&91;21&93;&91;22&93;} 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.^&91;23&93; 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^&91;24&93; and G_sα deficiency-caused failing mouse hearts.^&91;25&93; 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.^&91;26&93;

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

Further reading

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

External links

• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hyper-card GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview]

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