ArticleProceedings of the National Academy of Sciences of the United States of America2025
Resolving the structure and dynamics of the disordered C terminus of human cardiac troponin T and effects of cardiomyopathic mutations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Thin filament interaction and CaJournal of molecular and cellular cardiology · 2026Article
- Resolving the structure and dynamics of the disordered C terminus of human cardiac troponin T and effects of cardiomyopathic mutations.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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6 authors.
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Abstract
The C-terminal tail of cardiac troponin T (C-cTnT) inhibits thin filament activation and is a hotspot for cardiomyopathic mutations and variants. The mechanism whereby this region limits activation is not well understood. The last 16 C-terminal residues form a highly flexible and disordered domain and thus have been poorly resolved in studies to date. Using Time-Resolved fluorescence resonance energy transfer (TR-FRET) we resolved the structure of the disordered C-cTnT and studied the structural and dynamic effects of cardiomyopathic mutations on the region. For wildtype (WT) thin filaments, our data revealed a repositioning of cTnT-274 closer to cTnC when bound with calcium and myosin, while cTnT-283 did not move relative to cTnC. Myosin binding decreased the flexibility of cTnT-274 while having no effect on cTnT-283. We found that hypertrophic cardiomyopathy mutation cTnT-K273E decreased flexibility and placed the C-cTnT in an activated position in the blocked and closed states, resulting in increased actomyosin interactions in the absence of calcium; while dilated cardiomyopathy mutation cTnT-D270N increased flexibility and decreased the ability of the C-cTnT to reach its activated position in the open state but had no effect on actomyosin interactions. Our results demonstrate the WT C-cTnT undergoes a disordered to ordered transition upon myosin binding that is directly altered in the presence of cardiomyopathic mutations. These data provide a structural framework for the coupling of TR-FRET with high-resolution molecular dynamics as a tool for interrogating intermolecular interactions of intrinsically disordered proteins and protein complexes.
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