TNNT2

Last updated
Cardiac sarcomere structure, featuring troponin T Cardiac sarcomere structure.png
Cardiac sarcomere structure, featuring troponin T
TNNT2
Protein TNNT2 PDB 1j1d.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TNNT2 , CMD1D, CMH2, CMPD2, LVNC6, RCM3, TnTC, cTnT, troponin T2, cardiac type
External IDs OMIM: 191045 MGI: 104597 HomoloGene: 68050 GeneCards: TNNT2
Orthologs
SpeciesHumanMouse
Entrez

7139

21956

Ensembl

ENSG00000118194

ENSMUSG00000026414

UniProt

P45379

P50752

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC) Chr 1: 201.36 – 201.38 Mb Chr 1: 135.76 – 135.78 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. [5] [6] 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.

Contents

The TNNT2 gene is located at 1q32 in the human chromosomal genome, encoding the cardiac muscle isoform of troponin T (cTnT). Human cTnT is an ~36-kDa protein consisting of 297 amino acids including the first methionine with an isoelectric point (pI) of 4.88. It is the tropomyosin- binding and thin filament anchoring subunit of the troponin complex in cardiac muscle cells. [7] [8] [9] TNNT2 gene is expressed in vertebrate cardiac muscles and embryonic skeletal muscles. [8] [9] [10]

Structure

Cardiac TnT is a 35.9 kDa protein composed of 298 amino acids. [11] [12] Cardiac TnT is the largest of the three troponin subunits (cTnT, troponin I (TnI), troponin C (TnC)) on the actin thin filament of cardiac muscle. The structure of TnT is asymmetric; the globular C-terminal domain interacts with tropomyosin (Tm), TnI and TnC, and the N-terminal tether which strongly binds Tm. The N-terminal region of TnT is alternatively spliced, accounting for multiple isoforms observed in cardiac muscle. [13]

Function

As part of the Troponin complex, the function of cTnT is to regulate muscle contraction. The N-terminal region of TnT that strongly binds actin most likely moves with Tm and actin during strong myosin crossbridge binding and force generation. This region is likely involved in the transduction of cooperativity down the thin filament. [14] The C-terminal region of TnT constitutes part of the globular troponin complex domain, and participates in employing the calcium sensitivity of strong myosin crossbridge binding to the thin filament. [15]

Clinical significance

Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with restrictive [16] and dilated cardiomyopathy. Transcripts for this gene undergo alternative splicing that results in many tissue-specific isoforms, however, the full-length nature of some of these variants has not yet been determined. [17] Mutations of this gene may be associated with mild or absent hypertrophy and predominant restrictive disease, with a high risk of sudden cardiac death. [16] Advancement to dilated cardiomyopathy may be more rapid in patients with TNNT2 mutations than in those with myosin heavy chain mutations. [18] [19]

In patients with active chronic non-inflammatory myopathy and myositis, skeletal muscles are a significant source of cardiac troponin T without any cardiac involvement. It is advised to measure cardiac troponin I instead if a skeletal muscle disorder is suspected. [20]

Elevated levels after Covid-19 mRNA vaccinations

A study carried out by the University of Basel and the University Hospital of Basel found that a Covid-19 mRNA vaccination significantly elevates the cardiac troponin T levels in the blood stream. 3 % of the study subjects have shown elevated amounts of the protein after their 3rd vaccination. The effect was most pronounced among young men. It is not yet clear what the mechanism is, and the observed troponin levels were still much lower than in clinically significant heart disease. Given that previous studies only registered 35 cases of heart muscle inflammation per million subjects, the involved researchers were surprised by the results. [21]

Evolution

TnT TnI gene pairs.jpg

Three homologous genes have evolved in vertebrates encoding three muscle type- specific isoforms of TnT. [9] Each of the TnT isoform genes is linked in chromosomal DNA to a troponin I (TnI) isoform gene encoding the inhibitory subunit of the troponin complex to form three gene pairs: The fast skeletal muscle TnI (fsTnI)-fsTnT, slow skeletal muscle TnI (ssTnI)-cTnT, and cTnI-ssTnT pairs. Sequence and epitope conservation studies suggested that genes encoding the muscle type-specific TnT and TnI isoforms have originated from a TnI-like ancestor gene and duplicated and diversified from a fsTnI-like-fsTnT-like gene pair. [22]

TNNT2 gene phylogenic tree.jpg

The apparently scrambled linkage between ssTnI-cTnT and cTnI-ssTnT genes actually reflects original functional linkages as that TNNT2 gene is expressed together with ssTnI gene in embryonic cardiac muscle. [23] Protein sequence alignment demonstrated that TNNT2 gene is conserved in vertebrate species (Fig. 2) in the middle and C-terminal regions, while the three muscle type isoforms are significantly diverged. [8] [9]

Alternative splicing

Mammalian TNNT2 gene contains 14 constitutive exons and 3 alternatively spliced exons. [24] Exons 4 and 5 encoding the N-terminal variable region and exon 13 between the middle and C-terminal regions are alternatively spliced. [25] Exon 5 encodes a 9 or 10 amino acid segment that is highly acidic and negatively charged at physiological pH. [8] Exon 5 is expressed in embryonic heart, down-regulated and ceases express during postnatal development. [26]

Embryonic cTnT with more negative charge at the N-terminal region exerts higher calcium sensitivity of actomyosin ATPase activity and myofilament force production, compared with the adult cardiac TnT, as well as a higher tolerance to acidosis. [27]

TNNT2 gene is transiently expressed in embryonic and neonatal skeletal muscles in both avian and mammalian organisms. [23] [28] [29] When TNNT2 is expressed in neonatal skeletal muscle, the alternative splicing of exon 5 exhibits a synchronized regulation to that in the heart in a species-specific manner. [23] This phenomenon indicates that alternative splicing of TNNT2 pre-mRNA is under the control of a genetically built- in systemic biological clock.

Posttranslational modifications

Phosphorylation

Ser2 of cTnT at the N terminus is constitutively phosphorylated by unknown mechanisms. [7] cTnT has been found to be phosphorylated by PKC at Thr197, Ser201, Thr206, Ser208 and Thr287 in the C-terminal region. Phosphorylation of Thr206 alone was sufficient to reduce myofilament calcium sensitivity and force production. [30] [31] [32] [33] cTnT is also phosphorylated at Thr194 and Ser198 under stress conditions, [34] leading to attenuated cardiomyocyte contractility. Phosphorylation of cTnT at Ser278 and Thr287 by ROCK-II was shown to decrease myosin ATPase activity and myofilament force development in skinned cardiac muscle. [35] Table 1 summarizes the phosphorylation modifications of cTnT and possible functions.

O-linked GlcNAcylation

cTnT is increasingly modified at Ser190 by O-GlcNAcylation during the development of heart failure in rat, accompanied by decreased phosphorylation of Ser208. [33]

Proteolytic modification

In apoptotic cardiomyocytes, cTnT was cleaved by caspase 3 to generate a 25-kDa N-terminal truncated fragment. [36] This destructive fragmentation removes a part of the middle region tropomyosin binding site 1, [22] leading to attenuation of the myofilament force production by decreasing the myosin ATPase activity. [36]

In cardiac muscle under stress conditions, cardiac TnT is cleaved by calpain I, restrictively removing the entire N-terminal variable region. [37] [38] This proteolytic modification of cTnT occurs in cardiac muscle in acute ischemia-reperfusion or pressure overload. [39]

The restrictively N-terminal truncated cTnT remains functional in the myofilaments and leads to reduced contractile velocity of the ventricular muscle, which extends the rapid ejection phase and results in an increase in stroke volume, especially under increased afterload. [39] In vitro studies showed that N-terminal truncated cTnT preserved the overall cardiac myofilament calcium sensitivity and cooperativity, but altered TnT's binding affinities for tropomyosin, TnI and TnC proteins, [40] [41] and lead to slightly decreased maximum myosin ATPase activity and myofilament force production, which forms the basis of the selective decrease in contractile velocity of ventricular muscle to increase stroke volume without significant increase in energy expenditure. [39]

With the relatively short half life of cTnT in cardiomyocytes (3–4 days), [42] the N-terminal truncated cTnT would be replaced by newly synthesized intact cTnT in several days. Therefore, this mechanism provides a reversible posttranslational regulation to modulate cardiac function in adaptation to stress conditions.

Phosphorylation sites in cTnT in comparison with ssTnT and fsTnT
Phosphorylation siteKinaseFunctionReference
cTnTssTnTfsTnT
Ser2ccPKCUnknown [43] [44] [45]
Thr197nNPKCNo functional effect [31] [46]
Ser201nnPKCNo functional effect [31] [46]
Thr204nnPKCReduce Myosin ATPase activity, myofilament force production and Ca2+ sensitivity [46] [47] [48]
Thr204nnCaMK IIUnknown [49]
Thr204nnASK IReduce cardiomyocyte contractility [34]
Thr206PKCReduce Ca2+ sensitivity, actomyosin ATPase activity and tension development [31]
Ser208nnPKCReduce Myosin ATPase activity, alter myofilament Ca2+ sensitivity [46] [48] [50]
Ser208nnASK IReduce cardiomyocyte contractility [34]
Thr213ccPKCReduce Myosin ATPase activity, myofilament force production and Ca2+ sensitivity [51]
Thr213ccRaf-1Unknown [52]
Ser285ncPKCReduce Myosin ATPase activity, myofilament force production and Ca2+ sensitivity [50]
Ser285ncROCK-IIReduce myofilament force development, Myosin ATPase activity and Ca2+ sensitivity [35]
Thr294nnPKCReduce Myosin ATPase activity, myofilament force production and Ca2+ sensitivity [46] [47] [48] [50]
Thr294nnROCK-IIReduce myofilament force development, myosin ATPase activity and Ca2+ sensitivity [35]

The residues in cardiac TnT with phosphorylation regulations are summarized. The residue numbers for phosphorylatable serine and threonine are that in human cardiac TnT with the first methionine included. The phosphorylation of cardiac TnT at these residues is compared with the counterparts in fast TnT and slow TnT. C, conserved; N, non-conserved. Kinases responsible for each phosphorylation, functional effects, and references are also listed.

Mutations in cardiomyopathies

Point mutations in TNNT2 gene cause various types of cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). The table below summarizes representative TNNT2 mutations and abnormal splicings found in human and animal cardiomyopathies.

Representative TNNT2 mutations and abnormal splicings that cause cardiomyopathy
MutationDiagnosisReference
Ile79AsnHCM [53] [54] [55]
Arg92GlnHCM [53] [56]
Intron 16G1→A (D14 and D28+7)HCM [53]
Arg92LeuHCM [55] [57]
Arg92TrpHCM [18] [58] [59]
Arg94LeuHCM [55] [60]
Arg94CysHCM [61]
ΔE96RCM [62] [63]
Ala104ValHCM [64]
Phe110IleDCM [65] [66]
Arg130CysHCM [67]
Arg131TrpDCM [68] [69]
E136KRCM [70]
Arg141TrpDCM [71] [72]
DGlu160HCM [73]
Glu163ArgHCM [67]
Glu163LysHCM [65]
Ser179PheHCM [74]
Arg205LeuDCM [68]
DLys210DCM [75] [76] [77]
Glu244AspHCM [65]
Asp270AsnDCM [75]
Lys273GluDCM [19]
Arg278CysHCM [65] [78]

Amino Acid residues of mutations were numbered as in human cardiac TnT with the first methionine included. Mutations of cardiac TnT that caused cardiomyopathies were mostly found in the conserved middle and C-terminal regions.

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">MYH7</span> Protein-coding gene in the species Homo sapiens

MYH7 is a gene encoding a myosin heavy chain beta (MHC-β) isoform expressed primarily in the heart, but also in skeletal muscles. This isoform is distinct from the fast isoform of cardiac myosin heavy chain, MYH6, referred to as MHC-α. MHC-β is the major protein comprising the thick filament that forms the sarcomeres in cardiac muscle and plays a major role in cardiac muscle contraction.

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

Nebulette is a cardiac-specific isoform belonging to the nebulin family of proteins. It is encoded by the NEBL gene. This family is composed of 5 members: nebulette, nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of cardiac muscle and appears to regulate the length of actin thin filaments.

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

Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the PRKCE gene. PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulates muscle contraction through its actions at sarcomeric proteins, and PKCε modulates cardiac cell metabolism through its actions at mitochondria. PKCε is clinically significant in that it is a central player in cardioprotection against ischemic injury and in the development of cardiac hypertrophy.

<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">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">Telethonin</span>

Telethonin, also known as Tcap, is a protein that in humans is encoded by the TCAP gene. Telethonin is expressed in cardiac and skeletal muscle at Z-discs and functions to regulate sarcomere assembly, T-tubule function and apoptosis. Telethonin has been implicated in several diseases, including limb-girdle muscular dystrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy and idiopathic cardiomyopathy.

<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">MYH10</span> Protein-coding gene in the species Homo sapiens

Myosin-10 also known as myosin heavy chain 10 or non-muscle myosin IIB (NM-IIB) is a protein that in humans is encoded by the MYH10 gene. Non-muscle myosins are expressed in a wide variety of tissues, but NM-IIB is the only non-muscle myosin II isoform expressed in cardiac muscle, where it localizes to adherens junctions within intercalated discs. NM-IIB is essential for normal development of cardiac muscle and for integrity of intercalated discs. Mutations in MYH10 have been identified in patients with left atrial enlargement.

<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">MYH6</span> Protein-coding gene in the species Homo sapiens

Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene. This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome.

<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">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.

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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