TNNI3

Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3 gene.^[5][6] It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

TNNI3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1J1D, 1J1E, 1LXF, 1MXL, 1OZS, 2KGB, 2KRD, 2L1R, 2MZP, 4Y99
Identifiers
Aliases	TNNI3, CMD1FF, CMD2A, CMH7, RCM1, TNNC1, cTnI, troponin I3, cardiac type
External IDs	OMIM: 191044; MGI: 98783; HomoloGene: 309; GeneCards: TNNI3; OMA:TNNI3 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.42 Start 55,151,767 bp[1] End 55,157,773 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 A1|7 2.61 cM Start 4,521,304 bp[2] End 4,527,228 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart myocardium of left ventricle right auricle of heart right ventricle cardiac muscle tissue of right atrium vena cava right uterine tube gonad testicle muscle of thigh Top expressed in myocardium cardiac muscle tissue of left ventricle right ventricle interventricular septum atrium atrioventricular valve aortic valve endocardial cushion epithelium of stomach pyloric antrum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein kinase binding protein binding troponin T binding calcium-dependent protein binding calcium channel inhibitor activity protein domain specific binding troponin C binding actin binding metal ion binding actin filament binding Cellular component troponin complex sarcomere cytosol cytoplasm contractile fiber myofibril cardiac myofibril cardiac Troponin complex Biological process ventricular cardiac muscle tissue morphogenesis negative regulation of ATP-dependent activity vasculogenesis cardiac muscle contraction regulation of muscle contraction heart development muscle filament sliding heart contraction regulation of smooth muscle contraction striated muscle contraction regulation of systemic arterial blood pressure by ischemic conditions cellular calcium ion homeostasis skeletal muscle contraction regulation of cardiac muscle contraction by calcium ion signaling muscle contraction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7137 21954 Ensembl ENSG00000129991 ENSMUSG00000035458 UniProt P19429 Q6FGX2 P48787 RefSeq (mRNA) NM_000363 NM_009406 RefSeq (protein) NP_000354 NP_000354.4 NP_033432 Location (UCSC) Chr 19: 55.15 – 55.16 Mb Chr 7: 4.52 – 4.53 Mb PubMed search [3] [4]
Wikidata
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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

1. 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]
2. 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.
3. 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 (cTnI_1-192) in transgenic mouse heart resulted in a phenotype of myocardial stunning with systolic and diastolic dysfunctions.^[23] 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.^[24]
4. 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 G_sα 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]

Notes