Abstract
Troponin T (TnT) is the thin filament anchoring subunit of troponin complex and plays an organizer role in the Ca2+-regulation of striated muscle contraction. From an ancestral gene emerged ~ 700 million years ago in Bilateria, three homologous genes have evolved in vertebrates to encode muscle type-specific isoforms of TnT. Alternative splicing variants of TnT are present in vertebrate and invertebrate muscles to add functional diversity. While the C-terminal region of TnT is largely conserved, it contains an alternatively spliced segment emerged early in C. elegans, which has evolved into a pair of mutually exclusive exons in arthropods (10A and 10B of Drosophila TpnT gene) and vertebrates (16 and 17 of fast skeletal muscle Tnnt3 gene). The C-terminal alternatively spliced segment of TnT interfaces with the other two subunits of troponin with functional significance. The vertebrate cardiac TnT gene that emerged from duplication of the fast TnT gene has eliminated this alternative splicing by the fixation of an exon 17-like constitutive exon, indicating a functional value in slower and rhythmic contractions. The vertebrate slow skeletal muscle TnT gene that emerged from duplication of the cardiac TnT gene has the exon 17-like structure conserved, indicating its further function in sustained and fatigue resistant contractions. This functionality-based evolution is consistent with the finding that exon 10B-encoded segment of Drosophila TnT homologous to the exon 17-encoded segment of vertebrate fast TnT is selectively expressed in insect heart and leg muscles. The evolution of the C-terminal variable region of TnT demonstrates a submolecular mechanism in modifying striated muscle contractility and for the treatment of muscle and heart diseases.
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Abbreviations
- BSA:
-
Bovine serum albumin
- ELISA:
-
Enzyme-linked immunosorbent assay
- mAb:
-
Monoclonal antibody
- PBS:
-
Phosphate-buffered saline
- RT-PCR:
-
Reverse transcription-coupled PCR
- SDS-PAGE:
-
SDS–polyacrylamide gel electrophoresis
- TBS:
-
Tris-buffered saline
- TnC:
-
Troponin C
- TnI:
-
Troponin I
- TnT:
-
Troponin T
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Acknowledgements
Stephen Chong participated in this study when our research group was at the Evanston Northwestern Healthcare Research Institute. We thank Prof. Jim Lin at University of Iowa for the T12 and CH1 mAbs. This study was supported by grants from the National Institutes of Health (HL127691 and HL138007 to JPJ).
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Cao, T., Akhter, S. & **, JP. Early Divergence of the C-Terminal Variable Region of Troponin T Via a Pair of Mutually Exclusive Alternatively Spliced Exons Followed by a Selective Fixation in Vertebrate Heart. J Mol Evol 90, 452–467 (2022). https://doi.org/10.1007/s00239-022-10075-z
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DOI: https://doi.org/10.1007/s00239-022-10075-z