TNNI3

Troponin I type 3 (cardiac)
PDB rendering based on 1j1d.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1J1D​, 1J1E​, 1LXF​, 1MXL​, 1OZS​, 2KGB​, 2KRD​, 2L1R​, 2MZP​
Identifiers
Symbols	TNNI3 ; CMD1FF; CMD2A; CMH7; RCM1; TNNC1; cTnI
External IDs	OMIM: 191044 MGI: 98783 HomoloGene: 309 ChEMBL: 1741177 GeneCards: TNNI3 Gene
Gene ontology Molecular function • actin binding • protein binding • calcium channel inhibitor activity • protein kinase binding • protein domain specific binding • troponin C binding • troponin T binding • metal ion binding • calcium-dependent protein binding Cellular component • cytosol • troponin complex • sarcomere Biological process • vasculogenesis • regulation of systemic arterial blood pressure by ischemic conditions • cellular calcium ion homeostasis • regulation of smooth muscle contraction • heart development • muscle filament sliding • negative regulation of ATPase activity • ventricular cardiac muscle tissue morphogenesis • heart contraction • cardiac muscle contraction Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7137	21954
Ensembl	ENSG00000129991	ENSMUSG00000035458
UniProt	P19429	P48787
RefSeq (mRNA)	NM_000363	NM_009406
RefSeq (protein)	NP_000354	NP_033432
Location (UCSC)	Chr 19: 55.15 – 55.16 Mb	Chr 7: 4.52 – 4.52 Mb
PubMed search

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 (cTnI_1-192) in transgenic mouse heart resulted in a phenotype of myocardial stunning with systolic and diastolic dysfunctions.^[19] 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.^[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 G_sα 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]

References

Further reading

External links

• GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview

PDB gallery 1j1d: Crystal structure of the 46kDa domain of human cardiac troponin in the Ca2+ saturated form  1j1e: Crystal structure of the 52kDa domain of human cardiac troponin in the Ca2+ saturated form