TNNI3

Last updated
TNNI3
Protein TNNI3 PDB 1j1d.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TNNI3 , CMD1FF, CMD2A, CMH7, RCM1, TNNC1, cTnI, troponin I3, cardiac type
External IDs OMIM: 191044 MGI: 98783 HomoloGene: 309 GeneCards: TNNI3
Orthologs
SpeciesHumanMouse
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
View/Edit Human View/Edit Mouse

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.

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. 7-27 cTnI align.jpg
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 (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]
  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 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]

Notes

Related Research Articles

<span class="mw-page-title-main">Troponin</span> Protein complex

Troponin, or the troponin complex, is a complex of three regulatory proteins that are integral to muscle contraction in skeletal muscle and cardiac muscle, but not smooth muscle. Measurements of cardiac-specific troponins I and T are extensively used as diagnostic and prognostic indicators in the management of myocardial infarction and acute coronary syndrome. Blood troponin levels may be used as a diagnostic marker for stroke or other myocardial injury that is ongoing, although the sensitivity of this measurement is low.

<span class="mw-page-title-main">Phospholamban</span> Mammalian protein found in Homo sapiens

Phospholamban, also known as PLN or PLB, is a micropeptide protein that in humans is encoded by the PLN gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the calcium (Ca2+) pump in cardiac muscle cells.

<span class="mw-page-title-main">Troponin C</span> Protein family

Troponin C is a protein which is part of the troponin complex. It contains four calcium-binding EF hands, although different isoforms may have fewer than four functional calcium-binding subdomains. It is a component of thin filaments, along with actin and tropomyosin. It contains an N lobe and a C lobe. The C lobe serves a structural purpose and binds to the N domain of troponin I (TnI). The C lobe can bind either Ca2+ or Mg2+. The N lobe, which binds only Ca2+, is the regulatory lobe and binds to the C domain of troponin I after calcium binding.

<span class="mw-page-title-main">Troponin I</span> Muscle protein

Troponin I is a cardiac and skeletal muscle protein family. It is a part of the troponin protein complex, where it binds to actin in thin myofilaments to hold the actin-tropomyosin complex in place. Troponin I prevents myosin from binding to actin in relaxed muscle. When calcium binds to the troponin C, it causes conformational changes which lead to dislocation of troponin I. Afterwards, tropomyosin leaves the binding site for myosin on actin leading to contraction of muscle. The letter I is given due to its inhibitory character. It is a useful marker in the laboratory diagnosis of heart attack. It occurs in different plasma concentration but the same circumstances as troponin T - either test can be performed for confirmation of cardiac muscle damage and laboratories usually offer one test or the other.

<span class="mw-page-title-main">TNNT2</span> Protein-coding gene in the species Homo sapiens

Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.

<span class="mw-page-title-main">Ryanodine receptor 2</span> Transport protein and coding gene in humans

Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.

<span class="mw-page-title-main">TPM1</span> Protein-coding gene in the species Homo sapiens

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

<span class="mw-page-title-main">Myosin binding protein C, cardiac</span> Protein-coding gene in the species Homo sapiens

The myosin-binding protein C, cardiac-type is a protein that in humans is encoded by the MYBPC3 gene. This isoform is expressed exclusively in heart muscle during human and mouse development, and is distinct from those expressed in slow skeletal muscle (MYBPC1) and fast skeletal muscle (MYBPC2).

<span class="mw-page-title-main">Troponin C type 1</span> Protein-coding gene in the species Homo sapiens

Troponin C, also known as TN-C or TnC, is a protein that resides in the troponin complex on actin thin filaments of striated muscle and is responsible for binding calcium to activate muscle contraction. Troponin C is encoded by the TNNC1 gene in humans for both cardiac and slow skeletal muscle.

<span class="mw-page-title-main">TPM2</span> Protein-coding gene in the species Homo sapiens

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

<span class="mw-page-title-main">TNNI1</span> Protein-coding gene in the species Homo sapiens

Troponin I, slow skeletal muscle is a protein that in humans is encoded by the TNNI1 gene. It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

<span class="mw-page-title-main">TNNI2</span> Protein-coding gene in the species Homo sapiens

Troponin I, fast skeletal muscle is a protein that in humans is encoded by the TNNI2 gene.

<span class="mw-page-title-main">MYL2</span> Protein-coding gene in the species Homo sapiens

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene. This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).

<span class="mw-page-title-main">TNNT1</span> Protein-coding gene in the species Homo sapiens

Slow skeletal muscle troponin T (sTnT) is a protein that in humans is encoded by the TNNT1 gene.

<span class="mw-page-title-main">TNNT3</span> Protein-coding gene in the species Homo sapiens

Fast skeletal muscle troponin T (fTnT) is a protein that in humans is encoded by the TNNT3 gene.

<span class="mw-page-title-main">Troponin C, skeletal muscle</span> Protein-coding gene in the species Homo sapiens

Troponin C, skeletal muscle is a protein that in humans is encoded by the TNNC2 gene.

<span class="mw-page-title-main">Heart-type fatty acid binding protein</span> Protein-coding gene in the species Homo sapiens

Heart-type fatty acid binding protein (hFABP) also known as mammary-derived growth inhibitor is a protein that in humans is encoded by the FABP3 gene.

<span class="mw-page-title-main">TNNI3K</span> Protein-coding gene in the species Homo sapiens

TNNI3 interacting kinase is a protein that in humans is encoded by the TNNI3K gene.

<span class="mw-page-title-main">Calponin 1</span> Protein-coding gene in the species Homo sapiens

Calponin 1 is a basic smooth muscle protein that in humans is encoded by the CNN1 gene.

A8V is point mutation on Troponin C (cTNC) that leads to a hypertrophic cardiomyopathy. The coordinated cardiac muscle contraction is regulated by the troponin complex on thin filament (troponin C which is calcium binding, troponin T that plays the role with tropomyosin, and troponin I which has an inhibitory action annulating the S1 ATPase activity in the presence of tropomyosin and troponin and absence of Ca2+). This mutation is determined by the change of Alanine to Valine at nucleotide 23 from C to T. Patients with this type of mutation shows thickness on the left ventricle wall of around 18 mm, compared to the normal this thickness would be 12 mm. Also, A8V affects the Ca2+ binding affinity compared to normal genotype and increased sensitivity on force development.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000035458 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ↑ 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. PMID   9241277. S2CID   31578767.
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  18. 1 2 Zhang Z, Akhter S, Mottl S, Jin JP (Sep 2011). "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. doi:10.1111/j.1742-4658.2011.08250.x. PMC   3168705 . PMID   21777381.
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  24. ↑ Narolska NA, Piroddi N, Belus A, Boontje NM, Scellini B, Deppermann S, Zaremba R, Musters RJ, dos Remedios C, Jaquet K, Foster DB, Murphy AM, van Eyk JE, Tesi C, Poggesi C, van der Velden J, Stienen GJ (Oct 2006). "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. doi: 10.1161/01.RES.0000248753.30340.af . PMID   17023673. S2CID   22328470.
  25. ↑ Perry SV (Jan 1999). "Troponin I: inhibitor or facilitator". Molecular and Cellular Biochemistry. 190 (1–2): 9–32. doi:10.1023/A:1006939307715. PMID   10098965. S2CID   23721684.
  26. ↑ Chong SM, Jin JP (May 2009). "To investigate protein evolution by detecting suppressed epitope structures". Journal of Molecular Evolution. 68 (5): 448–60. Bibcode:2009JMolE..68..448C. doi:10.1007/s00239-009-9202-0. PMC   2752406 . PMID   19365646.
  27. ↑ Akhter S, Zhang Z, Jin JP (Feb 2012). "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. doi:10.1152/ajpheart.00637.2011. PMC   3322736 . PMID   22140044.
  28. ↑ Yu ZB, Zhang LF, Jin JP (May 2001). "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. doi: 10.1074/jbc.M011048200 . PMID   11278823. S2CID   19133505.
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