ORCID
0000-0002-3145-2072 (Risi), 0000-0003-1138-7565 (Galkin)
Document Type
Article
Publication Date
2025
DOI
10.3390/physchem5020016
Publication Title
Physchem
Volume
5
Issue
2
Pages
16 (1-18)
Abstract
Troponin C (TnC) is the Ca²⁺-sensing subunit of troponin that is responsible for activating thin filaments in striated muscle, and, in turn, for regulating the systolic and diastolic contractile function of cardiac muscle. The secondary structure of vertebrate TnC is mainly composed of α-helices, with nine helices named sequentially, starting from the amino terminus, from N to A–H. The N-helix is a 12-residue-long α-helix located at the extreme amino terminus of the protein and is the only helical structure that does not participate in forming Ca²⁺-binding EF-hands. Evolutionarily, the N-helix is found only in TnC from mammalian species and most other vertebrates and is not present in other Ca²⁺-binding protein members of the calmodulin (CaM) family. Furthermore, the primary sequence of the N-helix differs between the genetic isoforms of the fast skeletal TnC (sTnC) and cardiac/slow skeletal TnC (cTnC). The 3D location of the N-helix within the troponin complex is also distinct between skeletal and cardiac troponin. Physical chemistry and biophysical studies centered on the sTnC N-helix demonstrate that it is crucial to the thermal stability and Ca²⁺ sensitivity of thin filament-regulated MgATPase activity in solution and to isometric force generation in the sarcomere. Comparable studies on the cTnC N-helix have not yet been performed despite the identification of cardiomyopathy-associated genetic variants that affect the residues of cTnC’s N-helix. Here, we review the current status of the research on TnC’s N-helix and establish future directions to elucidate its functional significance.
Rights
© 2025 by the authors.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.
Data Availability
Article states: "No new data were generated for this article. All structure models used in this review are from PDB with the IDs labeled correspondingly in the text."
Original Publication Citation
Shi, Y., Blackwell, L. A., Schroy, R. K., Cleland, B. M., Risi, C. M., Parvatiyar, M. S., Pinto, J. R., Galkin, V. E., & Chase, P. B. (2025). The central role for troponin C amino-terminal ⍺-helix in vertebrate thin filiment Ca²⁺-activation. Physchem, 5(2), 1-18, Article 16. https://doi.org/10.3390/physchem5020016
Repository Citation
Shi, Y., Blackwell, L. A., Schroy, R. K., Cleland, B. M., Risi, C. M., Parvatiyar, M. S., Pinto, J. R., Galkin, V. E., & Chase, P. B. (2025). The central role for troponin C amino-terminal ⍺-helix in vertebrate thin filiment Ca²⁺-activation. Physchem, 5(2), 1-18, Article 16. https://doi.org/10.3390/physchem5020016
Video S1: Movement of the CTnC N-helix (magenta) upon Ca2+ binding to cTnC within the troponin complex on the cardiac thin filament; Video S2: Rotated view of the movement of the cTnC N-helix (magenta) upon Ca2+ binding to CTnC within the troponin complex on the cardiac thin filament. The videos show the dynamic rotation of the CTnC within the troponin complex on the cardiac thin filament. The videos show the dynamic rotation of the cTnC N-helix from Ca2+-free state (PDB 8UWW) to the fully activated state (PDB 8UZX); the two videos show the same Ca2+-dependent movements viewed from perspectives that are related by 90-degree rotation around the F-actin helical axis. The color scheme in the videos is the same as in Figure 4: Actin is gray, tropomyosin is green, cTnl is blue, cTnT is yellow, and the CTnc subunit is red, with the N-helix sequence highlighted in magenta.
Included in
Amino Acids, Peptides, and Proteins Commons, Cardiovascular System Commons, Musculoskeletal, Neural, and Ocular Physiology Commons, Musculoskeletal System Commons