TNNT2

1J1D, 1J1E, 4Y99713921956ENSG00000118194ENSMUSG00000026414P45379P50752NM_001276346NM_001276347NM_001130179NM_001130180NM_001130181NM_011619NP_001263275NP_001263276NP_001123651NP_001123652NP_001123653NP_035749Cardiac 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.1j1d: Crystal structure of the 46kDa domain of human cardiac troponin in the Ca2+ saturated form1j1e: Crystal structure of the 52kDa domain of human cardiac troponin in the Ca2+ saturated form 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. 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. TNNT2 gene is expressed in vertebrate cardiac muscles and embryonic skeletal muscles. Cardiac TnT is a 35.9 kDa protein composed of 298 amino acids. 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. 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. 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. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with restrictive 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. Mutations of this gene may be associated with mild or absent hypertrophy and predominant restrictive disease, with a high risk of sudden cardiac death. Advancement to dilated cardiomyopathy may be more rapid in patients with TNNT2 mutations than in those with myosin heavy chain mutations. Three homologous genes have evolved in vertebrates encoding three muscle type- specific isoforms of TnT. 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. 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. 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. Mammalian TNNT2 gene contains 14 constitutive exons and 3 alternatively spliced exons. Exons 4 and 5 encoding the N-terminal variable region and exon 13 between the middle and C-terminal regions are alternatively spliced. Exon 5 encodes a 9 or 10 amino acid segment that is highly acidic and negatively charged at physiological pH. Exon 5 is expressed in embryonic heart, down-regulated and ceases express during postnatal development. 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.