ArticleJournal of molecular and cellular cardiology2010
Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro.
Article in Journal of molecular and cellular cardiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 55 citations in OpenAlex.
- Biochemical characterization of cardiac α-actin mutations A21V and D26N implicated in hypertrophic cardiomyopathy.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Duality in disease: How two amino acid substitutions at actin residue 312 result in opposing forms of cardiomyopathy.The Journal of biological chemistry · 2024Article
- Cryo-EM structures of cardiac muscle α-actin mutants M305L and A331P give insights into the structural mechanisms of hypertrophic cardiomyopathy.European journal of cell biology · 2024Article
- A Cautionary Tale of Hypertrophic Cardiomyopathy-From "Benign" Left Ventricular Hypertrophy to Stroke, Atrial Fibrillation, and Molecular Genetic Diagnostics: A Case Report and Review of Literature.International journal of molecular sciences · 2024Review
- Assessing Cardiac Contractility From Single Molecules to Whole Hearts.JACC. Basic to translational science · 2024Review
- Motility Assay to Probe the Calcium Sensitivity of Myosin and Regulated Thin Filaments.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Purification of modified mammalian actin isoforms for in vitro reconstitution assays.European journal of cell biology · 2023Review
- A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue.Journal of molecular and cellular cardiology plus · 2022Article
- Functional Characterization of Cardiac Actin Mutants Causing Hypertrophic (p.A295S) and Dilated Cardiomyopathy (p.R312H and p.E361G).International journal of molecular sciences · 2022Article
- Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics.Frontiers in cardiovascular medicine · 2022Review
- Integration of Cardiac Actin Mutants Causing Hypertrophic (p.A295S) and Dilated Cardiomyopathy (p.R312H and p.E361G) into Cellular Structures.Antioxidants (Basel, Switzerland) · 2021Article
- Overexpression ofJournal of cardiovascular development and disease · 2020Article
- Actin Mutations and Their Role in Disease.International journal of molecular sciences · 2020Review
- Influence of cytoskeleton organization on recombinant protein expression by CHO cells.Biotechnology and bioengineering · 2020Article
- Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits.Stem cell reports · 2018Article
- The Molecular Mechanisms of Mutations in Actin and Myosin that Cause Inherited Myopathy.International journal of molecular sciences · 2018Review
- Classifying Cardiac Actin Mutations Associated With Hypertrophic Cardiomyopathy.Frontiers in physiology · 2018Review
- CaProceedings of the National Academy of Sciences of the United States of America · 2017Article
- Cardiac contractility, motor function, and cross-bridge kinetics in N47K-RLC mutant mice.The FEBS journal · 2017Article
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Abstract
Two cardiomyopathic mutations were expressed in human cardiac actin, using a Baculovirus/insect cell system; E99K is associated with hypertrophic cardiomyopathy whereas R312H is associated with dilated cardiomyopathy. The hypothesis that the divergent phenotypes of these two cardiomyopathies are associated with fundamental differences in the molecular mechanics and thin filament regulation of the underlying actin mutation was tested using the in vitro motility and laser trap assays. In the presence of troponin (Tn) and tropomyosin (Tm), beta-cardiac myosin moved both E99K and R312H thin filaments at significantly (p<0.05) slower velocities than wild type (WT) at maximal Ca(++). At submaximal Ca(++), R312H thin filaments demonstrated significantly increased Ca(++) sensitivity (pCa(50)) when compared to WT. Velocity as a function of ATP concentration revealed similar ATP binding rates but slowed ADP release rates for the two actin mutants compared to WT. Single molecule laser trap experiments performed using both unregulated (i.e. actin) and regulated thin filaments in the absence of Ca(++) revealed that neither actin mutation significantly affected the myosin's unitary step size (d) or duration of strong actin binding (t(on)) at 20 microM ATP. However, the frequency of individual strong-binding events in the presence of Tn and Tm, was significantly lower for E99K than WT at comparable myosin surface concentrations. The cooperativity of a second myosin head binding to the thin filament was also impaired by E99K. In conclusion, E99K inhibits the activation of the thin filament by myosin strong-binding whereas R312H demonstrates enhanced calcium activation.
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