TNNI2

Last updated

TNNI2
Protein TNNI2 PDB 1a2x.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TNNI2 , AMCD2B, DA2B, FSSV, fsTnI, troponin I2, fast skeletal type, DA2B1
External IDs OMIM: 191043; MGI: 105070; HomoloGene: 37752; GeneCards: TNNI2; OMA:TNNI2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7136

21953

Ensembl

ENSG00000130598
ENSG00000288219

ENSMUSG00000031097

UniProt

P48788

P13412

RefSeq (mRNA)

NM_003282
NM_001145829
NM_001145841

NM_009405

RefSeq (protein)

NP_001139301
NP_001139313
NP_003273

NP_033431

Location (UCSC) Chr 11: 1.84 – 1.84 Mb Chr 7: 142 – 142 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Troponin I, fast skeletal muscle is a protein that in humans is encoded by the TNNI2 gene. [5] [6]

Contents

The TNNI2 gene is located at 11p15.5 in the human chromosomal genome, encoding the fast twitch skeletal muscle troponin I (fsTnI). fsTnI is a 21.3 kDa protein consisting of 182 amino acids including the first methionine with an isoelectric point (pI) of 8.74. It is the inhibitory subunit of the troponin complex in fast twitch skeletal muscle fibers. [7]

Gene evolution

Figure 1: Evolutionary lineages of TnI-TnT gene pairs Troponin evolution.JPG
Figure 1: Evolutionary lineages of TnI-TnT gene pairs
Figure 2: Evolutionary lineage of vertebrate fsTnI isoforms deduced from alignment of amino acid sequences. 7-27 fsTnI align.jpg
Figure 2: Evolutionary lineage of vertebrate fsTnI isoforms deduced from alignment of amino acid sequences.

Three homologous genes have evolved in vertebrates, encoding three muscle type-specific isoforms of TnI. [8] [9] [10] Sequence analysis, immunological distance, and examination of evolutionarily suppressed conformational states showed that the TnI genes have evolved in close linkage with the genes encoding troponin T (TnT), another subunit of the troponin complex. [10] The fast TnI-fast TnT gene pair represents the original TnI and TnT genes (Fig. 1). The three muscle fiber type-specific TnI-TnT gene pairs were likely originated from a TnI-like ancestor gene that presumably duplicated to form a closely linked fast TnI-like and fast TnT-like gene pair. A later duplication events resulted in emergences of a slow TnI-like and cardiac TnT-like gene pair that was further duplicated to give rise of the present-day slow TnI-cardiac TnT and cardiac TnI-slow TnT gene pairs. The seemingly scrambled ssTnI and cTnI gene pair is actually functionally related as they co-express and form troponin complex in the embryonic heart. The overlapping of enhancer elements of the TnT gene promoter with the upstream TnI gene structure may be a critical factor in the preservation of the close linkage of TnI and TnT gene pairs [11]

The phylogenetic tree in Fig. 2 summarizes the evolutionary lineage of fsTnI isoforms in vertebrate species.

Phylogenetic analysis of vertebrate TnI isoforms demonstrated that each of the muscle type-specific isoforms is more conserved across species than the three isoforms in one given species, indicating early diverged functions of the muscle fiber type-specific isoforms as well as the conservation of functions for each muscle fiber type. [12]

Tissue distribution

Fast skeletal muscle TnI was first cloned from a skeletal muscle cDNA library. [13] It is generally observed that fsTnI is exclusively expressed in fast twitch skeletal muscle fibers. More recent studies reported that subunits of fast skeletal muscle troponin (fsTnI, fsTnT, fsTnC) were expressed at significant levels in smooth muscle cells of mouse blood vessels, [14] bladder and bronchi. [15] Expression of fsTnI was also found in non-muscle cells, such as human corneal epithelial cells [16] and cartilage. [17] [18] The function of fsTnI expressed in smooth muscle and non-muscle cells is unclear.

Protein structure and function

Figure 3: Conformational changes occurring in the troponin complex during muscle contraction and relaxation (modified from the model proposed by Vinogradova et al. Conformational change of troponin.JPG
Figure 3: Conformational changes occurring in the troponin complex during muscle contraction and relaxation (modified from the model proposed by Vinogradova et al.

Crystallographic structure of fsTnI in troponin complex from chicken fast skeletal muscle showed an overall structure [19] similar to that of cardiac troponin. [20] The inhibitory region of fsTnI was resolved in skeletal troponin whereas it was invisible in the cardiac troponin crystal structure. Based on the crystal structure, a schematic illustration (Fig. 3) was proposed to show the conformational changes in troponin during muscle activation and relaxation.

Posttranslational modifications

Phosphorylation: Ser118 of fsTnI, equivalent to Ser150 in cTnI, was reported as a phosphorylation substrate of AMPK. [21] As AMPK is a key regulator of cellular energetics, phosphorylation of this site may provide an adaptive mechanism during energy deprivation in both skeletal and cardiac muscles.

S-glutathionylation: fsTnI was found to be S-glutathionylated at Cys133 in rodent fast-twitch skeletal muscle and in human type II muscle fibers after exercise, which increased Ca2+ sensitivity of the contractile apparatus. [22]

Clinical significance

A missense mutation R174Q, a nonsense mutation R156X, and three single residue deletions DE167, DK175 and DK176, all in the C-terminal actin-tropomyosin interacting domain, have been found in patients with distal arthrogryposis. [23] [24] [25] [26]

Skeletal muscle TnI has been proposed as a sensitive and fast fiber-specific serum marker of skeletal muscle injury. [27] [28] fsTnI concentration in increased peripheral blood when fast twitch fibers were damaged. [28]

Notes

Related Research Articles

<span class="mw-page-title-main">Skeletal muscle</span> One of three major types of muscle

Skeletal muscle is one of the three types of vertebrate muscle tissue, the other being cardiac muscle and smooth muscle. They are part of the voluntary muscular system and typically are attached by tendons to bones of a skeleton. The skeletal muscle cells are much longer than in the other types of muscle tissue, and are also known as muscle fibers. The tissue of a skeletal muscle is striated – having a striped appearance due to the arrangement of the sarcomeres.

<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 myocarditis, 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">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">TNNI3</span> Protein-coding gene in the species Homo sapiens

Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3 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">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">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">Alpha-actinin-3</span> Mammalian protein found in Homo sapiens

Alpha-actinin-3, also known as alpha-actinin skeletal muscle isoform 3 or F-actin cross-linking protein, is a protein that in humans is encoded by the ACTN3 gene located on chromosome 11. All people have two copies (alleles) of this gene.

<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">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">MYL3</span> Protein-coding gene in the species Homo sapiens

Myosin essential light chain (ELC), ventricular/cardiac isoform is a protein that in humans is encoded by the MYL3 gene. This cardiac ventricular/slow skeletal ELC isoform is distinct from that expressed in fast skeletal muscle (MYL1) and cardiac atrial muscle (MYL4). Ventricular ELC is part of the myosin molecule and is important in modulating cardiac muscle contraction.

<span class="mw-page-title-main">MYL4</span> Protein-coding gene in the species Homo sapiens

Atrial Light Chain-1 (ALC-1), also known as Essential Light Chain, Atrial is a protein that in humans is encoded by the MYL4 gene. ALC-1 is expressed in fetal cardiac ventricular and fetal skeletal muscle, as well as fetal and adult cardiac atrial tissue. ALC-1 expression is reactivated in human ventricular myocardium in various cardiac muscle diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and congenital heart diseases.

<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">MYH1</span> Protein-coding gene in the species Homo sapiens

Myosin-1, also known as 'striated muscle myosin heavy chain 1', is a protein that in humans is encoded by the MYH1 gene. This gene is most highly expressed in fast type IIX/D muscle fibres of vertebrates and encodes a protein found uniquely in striated muscle; it is a class II myosin with a long coiled coil tail that dimerizes and should not be confused with 'Myosin 1' encoded by the MYO1 family of genes (MYO1A-MYO1H). Class I MYO1 genes function in many cell types throughout biology and are single-headed membrane-binding myosins that lack a long coiled coil tail.

<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">MYH3</span> Protein-coding gene in the species Homo sapiens

Myosin-3 is a protein that in humans is encoded by the MYH3 gene.

<span class="mw-page-title-main">MYL7</span> Protein-coding gene in the species Homo sapiens

Atrial Light Chain-2 (ALC-2) also known as Myosin regulatory light chain 2, atrial isoform (MLC2a) is a protein that in humans is encoded by the MYL7 gene. ALC-2 expression is restricted to cardiac muscle atria in healthy individuals, where it functions to modulate cardiac development and contractility. In human diseases, including hypertrophic cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy and others, ALC-2 expression is altered.

<span class="mw-page-title-main">MYBPC2</span> Protein-coding gene in the species Homo sapiens

Myosin binding protein C, fast type is a protein that in humans is encoded by the MYBPC2 gene.

References

  1. 1 2 3 ENSG00000288219 GRCh38: Ensembl release 89: ENSG00000130598, ENSG00000288219 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031097 – 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.
  5. ↑ Tiso N, Rampoldi L, Pallavicini A, Zimbello R, Pandolfo D, Valle G, Lanfranchi G, Danieli GA (Jan 1997). "Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast". Biochemical and Biophysical Research Communications. 230 (2): 347–50. doi:10.1006/bbrc.1996.5958. hdl: 11577/2466889 . PMID   9016781.
  6. ↑ "Entrez Gene: TNNI2 troponin I type 2 (skeletal, fast)".
  7. ↑ Jin JP, Zhang Z, Bautista JA (2008-01-01). "Isoform diversity, regulation, and functional adaptation of troponin and calponin". Critical Reviews in Eukaryotic Gene Expression. 18 (2): 93–124. doi:10.1615/critreveukargeneexpr.v18.i2.10. PMID   18304026.
  8. ↑ Hastings KE (Feb 1997). "Molecular evolution of the vertebrate troponin I gene family". Cell Structure and Function. 22 (1): 205–11. doi: 10.1247/csf.22.205 . PMID   9113408.
  9. ↑ 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.
  10. 1 2 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.
  11. ↑ Huang QQ, Jin JP (Dec 1999). "Preserved close linkage between the genes encoding troponin I and troponin T, reflecting an evolution of adapter proteins coupling the Ca(2+) signaling of contractility". Journal of Molecular Evolution. 49 (6): 780–8. Bibcode:1999JMolE..49..780H. doi:10.1007/pl00006600. PMID   10594179. S2CID   9839814.
  12. ↑ Jin JP, Chen A, Huang QQ (Jul 1998). "Three alternatively spliced mouse slow skeletal muscle troponin T isoforms: conserved primary structure and regulated expression during postnatal development". Gene. 214 (1–2): 121–9. doi:10.1016/s0378-1119(98)00214-5. PMID   9651500.
  13. ↑ Zhu L, Perez-Alvarado G, Wade R (Apr 1994). "Sequencing of a cDNA encoding the human fast-twitch skeletal muscle isoform of troponin I". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1217 (3): 338–40. doi:10.1016/0167-4781(94)90297-6. PMID   8148383.
  14. ↑ Moran CM, Garriock RJ, Miller MK, Heimark RL, Gregorio CC, Krieg PA (Aug 2008). "Expression of the fast twitch troponin complex, fTnT, fTnI and fTnC, in vascular smooth muscle". Cell Motility and the Cytoskeleton. 65 (8): 652–61. doi:10.1002/cm.20291. PMC   2570210 . PMID   18548613.
  15. ↑ Ju Y, Li J, Xie C, Ritchlin CT, Xing L, Hilton MJ, Schwarz EM (Sep 2013). "Troponin T3 expression in skeletal and smooth muscle is required for growth and postnatal survival: characterization of Tnnt3(tm2a(KOMP)Wtsi) mice". Genesis. 51 (9): 667–75. doi:10.1002/dvg.22407. PMC   3787964 . PMID   23775847.
  16. ↑ Kinoshita S, Adachi W, Sotozono C, Nishida K, Yokoi N, Quantock AJ, Okubo K (Sep 2001). "Characteristics of the human ocular surface epithelium". Progress in Retinal and Eye Research. 20 (5): 639–73. doi:10.1016/s1350-9462(01)00007-6. PMID   11470454. S2CID   25497205.
  17. ↑ Moses MA, Wiederschain D, Wu I, Fernandez CA, Ghazizadeh V, Lane WS, Flynn E, Sytkowski A, Tao T, Langer R (Mar 1999). "Troponin I is present in human cartilage and inhibits angiogenesis". Proceedings of the National Academy of Sciences of the United States of America. 96 (6): 2645–50. Bibcode:1999PNAS...96.2645M. doi: 10.1073/pnas.96.6.2645 . PMC   15822 . PMID   10077564.
  18. ↑ Li Q, Shen PY, Wu G, Chen XZ (Jan 2003). "Polycystin-2 interacts with troponin I, an angiogenesis inhibitor". Biochemistry. 42 (2): 450–7. doi:10.1021/bi0267792. PMID   12525172.
  19. ↑ PDB: 1YTZ ​; Vinogradova MV, Stone DB, Malanina GG, Karatzaferi C, Cooke R, Mendelson RA, Fletterick RJ (Apr 2005). "Ca(2+)-regulated structural changes in troponin". Proceedings of the National Academy of Sciences of the United States of America. 102 (14): 5038–43. Bibcode:2005PNAS..102.5038V. doi: 10.1073/pnas.0408882102 . PMC   555973 . PMID   15784741.
  20. ↑ Takeda S, Yamashita A, Maeda K, Maéda Y (Jul 2003). "Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form". Nature. 424 (6944): 35–41. Bibcode:2003Natur.424...35T. doi:10.1038/nature01780. PMID   12840750. S2CID   2174019.
  21. ↑ Sancho Solis R, Ge Y, Walker JW (May 2011). "A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I". Protein Science. 20 (5): 894–907. doi:10.1002/pro.623. PMC   3125873 . PMID   21416543.
  22. ↑ Mollica JP, Dutka TL, Merry TL, Lamboley CR, McConell GK, McKenna MJ, Murphy RM, Lamb GD (Mar 2012). "S-glutathionylation of troponin I (fast) increases contractile apparatus Ca2+ sensitivity in fast-twitch muscle fibres of rats and humans" (PDF). The Journal of Physiology. 590 (Pt 6): 1443–63. doi:10.1113/jphysiol.2011.224535. PMC   3382333 . PMID   22250211.
  23. ↑ Sung SS, Brassington AM, Grannatt K, Rutherford A, Whitby FG, Krakowiak PA, Jorde LB, Carey JC, Bamshad M (Mar 2003). "Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes". American Journal of Human Genetics. 72 (3): 681–90. doi:10.1086/368294. PMC   1180243 . PMID   12592607.
  24. ↑ Jiang M, Zhao X, Han W, Bian C, Li X, Wang G, Ao Y, Li Y, Yi D, Zhe Y, Lo WH, Zhang X, Li J (Sep 2006). "A novel deletion in TNNI2 causes distal arthrogryposis in a large Chinese family with marked variability of expression". Human Genetics. 120 (2): 238–42. doi:10.1007/s00439-006-0183-4. PMID   16802141. S2CID   6246993.
  25. ↑ Kimber E, Tajsharghi H, Kroksmark AK, Oldfors A, Tulinius M (Aug 2006). "A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis". Neurology. 67 (4): 597–601. doi:10.1212/01.wnl.0000230168.05328.f4. PMID   16924011. S2CID   72428621.
  26. ↑ Robinson P, Lipscomb S, Preston LC, Altin E, Watkins H, Ashley CC, Redwood CS (Mar 2007). "Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function". FASEB Journal. 21 (3): 896–905. doi: 10.1096/fj.06-6899com . PMID   17194691. S2CID   25491760.
  27. ↑ Simpson JA, Labugger R, Collier C, Brison RJ, Iscoe S, Van Eyk JE (Jun 2005). "Fast and slow skeletal troponin I in serum from patients with various skeletal muscle disorders: a pilot study". Clinical Chemistry. 51 (6): 966–72. doi: 10.1373/clinchem.2004.042671 . PMID   15833785.
  28. 1 2 Chapman DW, Simpson JA, Iscoe S, Robins T, Nosaka K (Jan 2013). "Changes in serum fast and slow skeletal troponin I concentration following maximal eccentric contractions". Journal of Science and Medicine in Sport. 16 (1): 82–5. doi: 10.1016/j.jsams.2012.05.006 . PMID   22795680.

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