Troponin T isoforms and posttranscriptional modifications: Evolution, regulation and function

Abstract

Troponin-mediated Ca²(+)-regulation governs the actin-activated myosin motor function which powers striated (skeletal and cardiac) muscle contraction. This review focuses on the structure-function relationship of troponin T, one of the three protein subunits of the troponin complex. Molecular evolution, gene regulation, alternative RNA splicing, and posttranslational modifications of troponin T isoforms in skeletal and cardiac muscles are summarized with emphases on recent research progresses. The physiological and pathophysiological significances of the structural diversity and regulation of troponin T are discussed for impacts on striated muscle function and adaptation in health and diseases.

Fig. 1. Structural and functional domains of TnT

This illustration outlines the structural and functional regions of TnT. The high resolution structure of partial troponin complex including a C-terminal segment of TnT that interacts with TnI and TnC as determined with crystallography is redrawn from published data (19). The chymotryptic cleavage site between the T1 and T2 fragments, the sites of cleavage in cardiac TnT by calpain I to selectively remove the N-terminal variable region (121) and by caspase 3 (120), the position of the Amish nemaline myopathy (ANM) nonsense mutation (52), and the alternatively spliced C-terminal variable region of fast TnT are indicated with arrows. The recently refined locations of the two tropomyosin-binding sites (24) are outlined.

Fig. 2. Evolutionary lineages of TnI-TnT genes

The evolution of TnI, TnT and the linked isoform gene pairs was established from data of sequence analysis, immunological distance, and experimental examination of evolutionarily suppressed conformational states (9). This evolutionary lineage began from a TnI-like ancestor gene that was duplicated to form a linked fast TnI-fast TnT-like gene pair. A later duplication event resulted in the emergences of a slow TnI-cardiac TnT-like gene pair that was further duplicated to give rise the present-day slow TnI-cardiac TnT and cardiac TnI-slow TnT gene pairs. This figure is duplicated with permission from a part of a figure published previously (9).

Fig. 3. Alternatively spliced exons of mammalian and avian fast, cardiac and slow TnT genes

The exon segments for the coding region of fast, cardiac and slow TnT genes are shown with the alternatively spliced exons represented by the filled boxes, among which the developmentally regulated exons are in solid black. The w, x (P), and y exons illustrated in the fast TnT structure are only found in avian species. The outlines demonstrate that the C-terminal and middle regions of TnT are highly conserved among the three fiber type-specific isoforms whereas the N-terminal region is highly variable. The alternative splicing of exon 6 in slow TNT gene using two acceptor sites is indicated with an arrowhead. The calpain I cleavage site that selectively removes the N-terminal variable region of cardiac TnT in stress conditions (121), the caspase 3 cleavage site in cardiac TnT (120), and the chymotrypsin cleavage site used to generate the T1 and T2 experimental fragments of fast TnT (10) are also indicated with arrowheads