ArticleArchives of biochemistry and biophysics2014
Energy landscapes reveal the myopathic effects of tropomyosin mutations.
Article in Archives of biochemistry and biophysics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed.
- Protein Sequencing with Single Amino Acid Resolution Discerns Peptides That Discriminate Tropomyosin Proteoforms.Journal of proteome research · 2025Article
- Screening single nucleotide changes to tropomyosin to identify novel cardiomyopathy mutants.Journal of molecular and cellular cardiology · 2025Article
- Dual role of Tropomyosin-R160 in thin filament regulation: Insights into phosphorylation-dependent cardiac relaxation and cardiomyopathy mechanisms.Archives of biochemistry and biophysics · 2025Article
- Article
- Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants.The Journal of clinical investigation · 2024Article
- Philament: A filament tracking program to quickly and accurately analyze in vitro motility assays.Biophysical reports · 2024Article
- Glutamate 139 of tropomyosin is critical for cardiac thin filament blocked-state stabilization.Journal of molecular and cellular cardiology · 2024Article
- Troponin and a Myopathy-Linked Mutation inInternational journal of molecular sciences · 2023Article
- A Novel Variant inInternational journal of molecular sciences · 2023Article
- Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.PNAS nexus · 2023Article
- Myosin loop-4 is critical for optimal tropomyosin repositioning on actin during muscle activation and relaxation.The Journal of general physiology · 2023Article
- Bridging the muscle genome to phenome across multiple biological scales.The Journal of experimental biology · 2022Article
- Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics.Frontiers in cardiovascular medicine · 2022Review
- Computational and biophysical determination of pathogenicity of variants of unknown significance in cardiac thin filament.JCI insight · 2021Article
- Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.The Journal of general physiology · 2021Article
- Mutations Q93H and E97K inInternational journal of molecular sciences · 2021Article
- M8R tropomyosin mutation disrupts actin binding and filament regulation: The beginning affects the middle and end.The Journal of biological chemistry · 2020Article
- Looking for Targets to Restore the Contractile Function in Congenital Myopathy Caused by GlnInternational journal of molecular sciences · 2020Article
- A new twist on tropomyosin binding to actin filaments: perspectives on thin filament function, assembly and biomechanics.Journal of muscle research and cell motility · 2020Review
- Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1.Journal of muscle research and cell motility · 2020Review
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Authors and funding
5 authors.
Funding
Abstract
Striated muscle contraction is regulated by an interaction network connecting the effects of troponin, Ca(2+), and myosin-heads to the azimuthal positioning of tropomyosin along thin filaments. Many missense mutations, located at the actin-tropomyosin interface, however, reset the regulatory switching mechanism either by weakening or strengthening residue-specific interactions, leading to hyper- or hypo-contractile pathologies. Here, we compute energy landscapes for the actin-tropomyosin interface and quantify contributions of single amino acid residues to actin-tropomyosin binding. The method is a useful tool to assess effects of actin and tropomyosin mutations, potentially relating initial stages of myopathy to alterations in thin filament stability and regulation. Landscapes for mutant filaments linked to hyper-contractility provide a simple picture that describes a decrease in actin-tropomyosin interaction energy. Destabilizing the blocked (relaxed)-state parallels previously noted enhanced Ca(2+)-sensitivity conferred by these mutants. Energy landscapes also identify post-translational modifications that can rescue regulatory imbalances. For example, cardiomyopathy-associated E62Q tropomyosin mutation weakens actin-tropomyosin interaction, but phosphorylation of neighboring S61 rescues the binding-deficit, results confirmed experimentally by in vitro motility assays. Unlike results on hyper-contractility-related mutants, landscapes for tropomyosin mutants tied to hypo-contractility do not present a straightforward picture. These mutations may affect other components of the regulatory network, e.g., troponin-tropomyosin signaling.
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