ArticleBiochemistry2012
Structural and functional consequences of the cardiac troponin C L48Q Ca(2+)-sensitizing mutation.
Article in Biochemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
- Calcium has a direct effect on thick filament activation in porcine myocardium.The Journal of general physiology · 2024Article
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscles and Structure-Activity Relationship.Journal of chemical information and modeling · 2023Article
- Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations.Journal of chemical information and modeling · 2023Article
- Using Multiscale Simulations as a Tool to Interpret Equatorial X-ray Fiber Diffraction Patterns from Skeletal Muscle.International journal of molecular sciences · 2023Article
- Machine learning meets Monte Carlo methods for models of muscle's molecular machinery to classify mutations.The Journal of general physiology · 2023Article
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship.bioRxiv : the preprint server for biology · 2023Article
- Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.Journal of chemical information and modeling · 2022Article
- The effect of MgThe FEBS journal · 2022Article
- Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin.Journal of chemical information and modeling · 2022Article
- Effect of Myosin Isoforms on Cardiac Muscle Twitch of Mice, Rats and Humans.International journal of molecular sciences · 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
- The effect of variable troponin C mutation thin filament incorporation on cardiac muscle twitch contractions.Journal of molecular and cellular cardiology · 2021Article
- Multiscale modeling of twitch contractions in cardiac trabeculae.The Journal of general physiology · 2021Article
- Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts.JCI insight · 2020Article
- 3-Chlorodiphenylamine activates cardiac troponin by a mechanism distinct from bepridil or TFP.The Journal of general physiology · 2019Article
- Computational Studies of Cardiac and Skeletal Troponin.Frontiers in molecular biosciences · 2019Review
- Molecular Dynamics and Umbrella Sampling Simulations Elucidate Differences in Troponin C Isoform and Mutant Hydrophobic Patch Exposure.The journal of physical chemistry. B · 2018Article
- Changes in the dynamics of the cardiac troponin C molecule explain the effects of CaThe Journal of biological chemistry · 2017Article
- Effects of Cardiac Troponin I Mutation P83S on Contractile Properties and the Modulation by PKA-Mediated Phosphorylation.The journal of physical chemistry. B · 2016Article
- Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation-An Integrated Multiscale Modeling Study.The journal of physical chemistry. B · 2016Article
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Authors and funding
10 authors.
Funding
Abstract
Calcium binding to the regulatory domain of cardiac troponin C (cNTnC) causes a conformational change that exposes a hydrophobic surface to which troponin I (cTnI) binds, prompting a series of protein-protein interactions that culminate in muscle contraction. A number of cTnC variants that alter the Ca(2+) sensitivity of the thin filament have been linked to disease. Tikunova and Davis engineered a series of cNTnC mutations that altered Ca(2+) binding properties and studied the effects on the Ca(2+) sensitivity of the thin filament and contraction [Tikunova, S. B., and Davis, J. P. (2004) J. Biol. Chem. 279, 35341-35352]. One of the mutations they engineered, the L48Q variant, resulted in a pronounced increase in the cNTnC Ca(2+) binding affinity and Ca(2+) sensitivity of cardiac muscle force development. In this work, we sought structural and mechanistic explanations for the increased Ca(2+) sensitivity of contraction for the L48Q cNTnC variant, using an array of biophysical techniques. We found that the L48Q mutation enhanced binding of both Ca(2+) and cTnI to cTnC. Nuclear magnetic resonance chemical shift and relaxation data provided evidence that the cNTnC hydrophobic core is more exposed with the L48Q variant. Molecular dynamics simulations suggest that the mutation disrupts a network of crucial hydrophobic interactions so that the closed form of cNTnC is destabilized. The findings emphasize the importance of cNTnC's conformation in the regulation of contraction and suggest that mutations in cNTnC that alter myofilament Ca(2+) sensitivity can do so by modulating Ca(2+) and cTnI binding.
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