TNNT2

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.

Cardiac sarcomere structure, featuring troponin T

TNNT2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1J1D, 1J1E, 4Y99
Identifiers
Aliases	TNNT2, CMD1D, CMH2, CMPD2, LVNC6, RCM3, TnTC, cTnT, troponin T2, cardiac type
External IDs	OMIM: 191045; MGI: 104597; HomoloGene: 68050; GeneCards: TNNT2; OMA:TNNT2 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q32.1 Start 201,359,008 bp[1] End 201,377,764 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 E4|1 59.32 cM Start 135,764,092 bp[2] End 135,779,998 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart right auricle left ventricle sural nerve right frontal lobe skin of leg Brodmann area 9 skin of abdomen anterior cingulate cortex right lung Top expressed in atrioventricular valve atrium myocardium of ventricle left ventricle aortic valve cardiac muscles interventricular septum cardiac muscle tissue of left ventricle right ventricle endocardial cushion More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein-macromolecule adaptor activity ATPase activity protein binding actin binding tropomyosin binding troponin C binding troponin I binding calcium ion binding calcium-dependent ATPase activity Cellular component cytosol troponin complex sarcomere striated muscle thin filament myofibril cardiac myofibril cardiac Troponin complex Biological process regulation of muscle contraction muscle contraction regulation of heart contraction positive regulation of ATP-dependent activity negative regulation of ATP-dependent activity response to calcium ion ventricular cardiac muscle tissue morphogenesis actin crosslink formation muscle filament sliding regulation of muscle filament sliding speed cardiac muscle contraction protein heterooligomerization skeletal muscle contraction sarcomere organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7139 21956 Ensembl ENSG00000118194 ENSMUSG00000026414 UniProt P45379 P50752 RefSeq (mRNA) NM_000364 NM_001001430 NM_001001431 NM_001001432 NM_001276345 NM_001276346 NM_001276347 NM_001130174 NM_001130175 NM_001130176 NM_001130177 NM_001130178 NM_001130179 NM_001130180 NM_001130181 NM_011619 RefSeq (protein) NP_000355 NP_001001430 NP_001001431 NP_001001432 NP_001263274 NP_001263275 NP_001263276 NP_001123646 NP_001123647 NP_001123648 NP_001123649 NP_001123650 NP_001123651 NP_001123652 NP_001123653 NP_035749 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

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

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]

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 site			Kinase	Function	Reference
cTnT	ssTnT	fsTnT
Ser2	c	c	PKC	Unknown	[43][44][45]
Thr197	n	N	PKC	No functional effect	[31][46]
Ser201	n	n	PKC	No functional effect	[31][46]
Thr204	n	n	PKC	Reduce Myosin ATPase activity, myofilament force production and Ca2+ sensitivity	[46][47][48]
Thr204	n	n	CaMK II	Unknown	[49]
Thr204	n	n	ASK I	Reduce cardiomyocyte contractility	[34]
Thr206			PKC	Reduce Ca2+ sensitivity, actomyosin ATPase activity and tension development	[31]
Ser208	n	n	PKC	Reduce Myosin ATPase activity, alter myofilament Ca2+ sensitivity	[46][48][50]
Ser208	n	n	ASK I	Reduce cardiomyocyte contractility	[34]
Thr213	c	c	PKC	Reduce Myosin ATPase activity, myofilament force production and Ca2+ sensitivity	[51]
Thr213	c	c	Raf-1	Unknown	[52]
Ser285	n	c	PKC	Reduce Myosin ATPase activity, myofilament force production and Ca2+ sensitivity	[50]
Ser285	n	c	ROCK-II	Reduce myofilament force development, Myosin ATPase activity and Ca2+ sensitivity	[35]
Thr294	n	n	PKC	Reduce Myosin ATPase activity, myofilament force production and Ca2+ sensitivity	[46][47][48][50]
Thr294	n	n	ROCK-II	Reduce 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

Mutation	Diagnosis	Reference
Ile79Asn	HCM	[53][54][55]
Arg92Gln	HCM	[53][56]
Intron 16G1→A (D14 and D28+7)	HCM	[53]
Arg92Leu	HCM	[55][57]
Arg92Trp	HCM	[18][58][59]
Arg94Leu	HCM	[55][60]
Arg94Cys	HCM	[61]
ΔE96	RCM	[62][63]
Ala104Val	HCM	[64]
Phe110Ile	DCM	[65][66]
Arg130Cys	HCM	[67]
Arg131Trp	DCM	[68][69]
E136K	RCM	[70]
Arg141Trp	DCM	[71][72]
DGlu160	HCM	[73]
Glu163Arg	HCM	[67]
Glu163Lys	HCM	[65]
Ser179Phe	HCM	[74]
Arg205Leu	DCM	[68]
DLys210	DCM	[75][76][77]
Glu244Asp	HCM	[65]
Asp270Asn	DCM	[75]
Lys273Glu	DCM	[19]
Arg278Cys	HCM	[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

References

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External links

• Mass spectrometry characterization of human TNNT2 at COPaKB Archived 2016-03-05 at the Wayback Machine
• GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview
• Overview of all the structural information available in the PDB for UniProt: P45379 (Troponin T, cardiac muscle) at the PDBe-KB.