ArticleProceedings of the National Academy of Sciences of the United States of America2014
The cardiac-specific N-terminal region of troponin I positions the regulatory domain of troponin C.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 61 citations in OpenAlex.
- Desensitization of the Cardiac Troponin Complex by TnI Phosphorylation and Epigallocatechin-3-Gallate.ACS omega · 2026Article
- Nsun2 controls cardiac homeostasis and hypertrophic response by regulating PRKACA expression.Theranostics · 2025Article
- Arg92Leu-cTnT Alters the cTnC-cTnI Interface Disrupting PKA-Mediated Relaxation.Circulation research · 2024Article
- Glutamate 139 of tropomyosin is critical for cardiac thin filament blocked-state stabilization.Journal of molecular and cellular cardiology · 2024Article
- Structure and dynamics of endogenous cardiac troponin complex in human heart tissue captured by native nanoproteomics.Nature communications · 2023Article
- Modulation of Structure and Dynamics of Cardiac Troponin by Phosphorylation and Mutations Revealed by Molecular Dynamics Simulations.The journal of physical chemistry. B · 2023Article
- Recent studies of the molecular mechanism of lusitropy due to phosphorylation of cardiac troponin I by protein kinase A.Journal of muscle research and cell motility · 2023Review
- Mouse Models of Cardiomyopathies Caused by Mutations in Troponin C.International journal of molecular sciences · 2023Review
- The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans.Nature communications · 2023Article
- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- A Revised Perspective on the Evolution of Troponin I and Troponin T Gene Families in Vertebrates.Genome biology and evolution · 2023Article
- Modulation of cardiac thin filament structure by phosphorylated troponin-I analyzed by protein-protein docking and molecular dynamics simulation.Archives of biochemistry and biophysics · 2022Article
- Physiological and pathological roles of protein kinase A in the heart.Cardiovascular research · 2022Review
- Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy.Chemical science · 2021Article
- Troponin structure and function: a view of recent progress.Journal of muscle research and cell motility · 2020Review
- Myosin and Other Energy-Transducing ATPases: Structural Dynamics Studied by Electron Paramagnetic Resonance.International journal of molecular sciences · 2020Review
- Structural Dynamics of the N-Extension of Cardiac Troponin I Complexed with Troponin C by Site-Directed Spin Labeling Electron Paramagnetic Resonance.Scientific reports · 2019Article
- FRET-based analysis of the cardiac troponin T linker region reveals the structural basis of the hypertrophic cardiomyopathy-causing Δ160E mutation.The Journal of biological chemistry · 2019Article
- Small molecule studies: the fourth wave of muscle research.Journal of muscle research and cell motility · 2019Article
- The missing links within troponin.Archives of biochemistry and biophysics · 2019Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
Abstract
The cardiac isoform of troponin I (cTnI) has a unique 31-residue N-terminal region that binds cardiac troponin C (cTnC) to increase the calcium sensitivity of the sarcomere. The interaction can be abolished by cTnI phosphorylation at Ser22 and Ser23, an important mechanism for regulating cardiac contractility. cTnC contains two EF-hand domains (the N and C domain of cTnC, cNTnC and cCTnC) connected by a flexible linker. Calcium binding to either domain favors an "open" conformation, exposing a large hydrophobic surface that is stabilized by target binding, cTnI[148-158] for cNTnC and cTnI[39-60] for cCTnC. We used multinuclear multidimensional solution NMR spectroscopy to study cTnI[1-73] in complex with cTnC. cTnI[39-60] binds to the hydrophobic face of cCTnC, stabilizing an alpha helix in cTnI[41-67] and a type VIII turn in cTnI[38-41]. In contrast, cTnI[1-37] remains disordered, although cTnI[19-37] is electrostatically tethered to the negatively charged surface of cNTnC (opposite its hydrophobic surface). The interaction does not directly affect the calcium binding affinity of cNTnC. However, it does fix the positioning of cNTnC relative to the rest of the troponin complex, similar to what was previously observed in an X-ray structure [Takeda S, et al. (2003) Nature 424(6944):35-41]. Domain positioning impacts the effective concentration of cTnI[148-158] presented to cNTnC, and this is how cTnI[19-37] indirectly modulates the calcium affinity of cNTnC within the context of the cardiac thin filament. Phosphorylation of cTnI at Ser22/23 disrupts domain positioning, explaining how it impacts many other cardiac regulatory mechanisms, like the Frank-Starling law of the heart.
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