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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1073\/pnas.2425343122","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T11:39:52Z","timestamp":1751974792000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Resolving the structure and dynamics of the disordered C terminus of human cardiac troponin T and effects of cardiomyopathic mutations"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0258-8041","authenticated-orcid":false,"given":"Garrett S.","family":"Crosby","sequence":"first","affiliation":[{"name":"Department of Physiological Sciences, University of Arizona","place":["Tucson"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5577-4983","authenticated-orcid":false,"given":"Bai","family":"Hei","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Arizona","place":["Tucson"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1107-4027","authenticated-orcid":false,"given":"Melissa L.","family":"Lynn","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Arizona","place":["Tucson"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1275-9152","authenticated-orcid":false,"given":"Ananya","family":"Chakraborti","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Arizona","place":["Tucson"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven D.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Arizona","place":["Tucson"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4291-4882","authenticated-orcid":false,"given":"Jil C.","family":"Tardiff","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Arizona","place":["Tucson"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.224170"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.02.011"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(93)81110-X"},{"key":"e_1_3_4_4_2","first-page":"49","article-title":"Skeletal and cardiac muscle contractile activation: Tropomyosin \u201crocks and rolls\u201d","volume":"16","author":"Gordon A. 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