ArticleThe Journal of biological chemistry2012
Correlation of molecular and functional effects of mutations in cardiac troponin T linked to familial hypertrophic cardiomyopathy: an integrative in silico/in vitro approach.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 38 citations in OpenAlex.
- The transmission of mutation effects in a multiprotein machine: A comprehensive metadynamics study of the cardiac thin filament.Protein science : a publication of the Protein Society · 2024Article
- Motility Assay to Probe the Calcium Sensitivity of Myosin and Regulated Thin Filaments.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Sarcomeric gene variants among Indians with hypertrophic cardiomyopathy: A scoping review.The Indian journal of medical research · 2023Article
- A troponin T variant linked with pediatric dilated cardiomyopathy reduces the coupling of thin filament activation to myosin and calcium binding.Molecular biology of the cell · 2021Article
- A comprehensive guide to genetic variants and post-translational modifications of cardiac troponin C.Journal of muscle research and cell motility · 2021Article
- Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine.The Journal of general physiology · 2021Article
- Article
- Docking Troponin T onto the Tropomyosin Overlapping Domain of Thin Filaments.Biophysical journal · 2020Article
- Computational Studies of Cardiac and Skeletal Troponin.Frontiers in molecular biosciences · 2019Review
- Mechanism of Cardiac Tropomyosin Transitions on Filamentous Actin As Revealed by All-Atom Steered Molecular Dynamics Simulations.The journal of physical chemistry letters · 2018Article
- Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Pathogenesis of Hypertrophic Cardiomyopathy is Mutation Rather Than Disease Specific: A Comparison of the Cardiac Troponin T E163R and R92Q Mouse Models.Journal of the American Heart Association · 2017Article
- Clinically Divergent Mutation Effects on the Structure and Function of the Human Cardiac Tropomyosin Overlap.Biochemistry · 2017Article
- The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy.Journal of molecular and cellular cardiology · 2017Article
- Genomic Insights into Cardiomyopathies: A Comparative Cross-Species Review.Veterinary sciences · 2017Review
- Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy.Circulation. Heart failure · 2017Article
- Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants-Genotype to Cellular Phenotype.Frontiers in physiology · 2017Review
- Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility.Archives of biochemistry and biophysics · 2016Review
- Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy: An In Vitro Analysis From an RBM20 Patient-Derived iPSC Model.Clinical and translational science · 2016Article
- Atomic resolution probe for allostery in the regulatory thin filament.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Nearly 70% of all of the known cTnT mutations that cause familial hypertrophic cardiomyopathy fall within the TNT1 region that is critical to cTn-Tm binding. The high resolution structure of this domain has not been determined, and this lack of information has hindered structure-function analysis. In the current study, a coupled computational experimental approach was employed to correlate changes in cTnT dynamics to basic function using the regulated in vitro motility assay (R-IVM). An in silico approach to calculate forces in terms of a bending coordinate was used to precisely identify decreases in bending forces at residues 105 and 106 within the proposed cTnT "hinge" region. Significant functional changes were observed in multiple functional properties, including a decrease in the cooperativity of calcium activation, the calcium sensitivity of sliding speed, and maximum sliding speed. Correlation of the computational and experimental findings revealed an association between TNT1 flexibility and the cooperativity of thin filament calcium activation where an increase in flexibility led to a decrease in cooperativity. Further analysis of the primary sequence of the TNT1 region revealed a unique pattern of conserved charged TNT1 residues altered by the R92W and R92L mutations and may represent the underlying "structure" modulating this central functional domain. These data provide a framework for further integrated in silico/in vitro approaches that may be extended into a high-throughput predictive screen to overcome the current structural limitations in linking molecular phenotype to genotype in thin filament cardiomyopathies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.