ArticleBiophysical journal2014
Computational studies of the effect of the S23D/S24D troponin I mutation on cardiac troponin structural dynamics.
Article in Biophysical journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 55 citations in OpenAlex.
- Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis.Frontiers in cardiovascular medicine · 2022Pooled it
- Desensitization of the Cardiac Troponin Complex by TnI Phosphorylation and Epigallocatechin-3-Gallate.ACS omega · 2026Article
- Dual role of Tropomyosin-R160 in thin filament regulation: Insights into phosphorylation-dependent cardiac relaxation and cardiomyopathy mechanisms.Archives of biochemistry and biophysics · 2025Article
- Troponin I - a comprehensive review of its function, structure, evolution, and role in muscle diseases.Animal cells and systems · 2025Review
- Focus on cardiac troponin complex: From gene expression to cardiomyopathy.Genes & diseases · 2024Review
- 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
- 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
- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.Journal of chemical information and modeling · 2022Article
- Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin.Journal of chemical information and modeling · 2022Article
- 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
- Understanding the molecular mechanism of endothelin ETBiophysical journal · 2022Article
- Computational Methods Elucidate Consequences of Mutations and Post-translational Modifications on Troponin I Effective Concentration to Troponin C.The journal of physical chemistry. B · 2021Article
- Adaptative Steered Molecular Dynamics Study of Mutagenesis Effects on Calcium Affinity in the Regulatory Domain of Cardiac Troponin C.Journal of chemical information and modeling · 2021Article
- Structural Changes beyond the EF-Hand Contribute to Apparent Calcium Binding Affinities: Insights from Parvalbumins.The journal of physical chemistry. B · 2021Article
- Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy.Chemical science · 2021Article
- NHJournal of cellular signaling · 2021Article
- Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts.JCI insight · 2020Article
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
During β-adrenergic stimulation, cardiac troponin I (cTnI) is phosphorylated by protein kinase A (PKA) at sites S23/S24, located at the N-terminus of cTnI. This phosphorylation has been shown to decrease KCa and pCa50, and weaken the cTnC-cTnI (C-I) interaction. We recently reported that phosphorylation results in an increase in the rate of early, slow phase of relaxation (kREL,slow) and a decrease in its duration (tREL,slow), which speeds up the overall relaxation. However, as the N-terminus of cTnI (residues 1-40) has not been resolved in the whole cardiac troponin (cTn) structure, little is known about the molecular-level behavior within the whole cTn complex upon phosphorylation of the S23/S24 residues of cTnI that results in these changes in function. In this study, we built up the cTn complex structure (including residues cTnC 1-161, cTnI 1-172, and cTnT 236-285) with the N-terminus of cTnI. We performed molecular-dynamics (MD) simulations to elucidate the structural basis of PKA phosphorylation-induced changes in cTn structure and Ca(2+) binding. We found that introducing two phosphomimic mutations into sites S23/S24 had no significant effect on the coordinating residues of Ca(2+) binding site II. However, the overall fluctuation of cTn was increased and the C-I interaction was altered relative to the wild-type model. The most significant changes involved interactions with the N-terminus of cTnI. Interestingly, the phosphomimic mutations led to the formation of intrasubunit interactions between the N-terminus and the inhibitory peptide of cTnI. This may result in altered interactions with cTnC and could explain the increased rate and decreased duration of slow-phase relaxation seen in myofibrils.
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Registered trials
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