{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:08:56Z","timestamp":1783555736875,"version":"3.55.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"1","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,1,7]]},"abstract":"<jats:p>The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone \u03b2 receptor (TR\u03b2) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic \u03b1-helix at the carboxyl terminus of TR\u03b2 and the position of the homologous residue in the crystal structure of TR\u03b1 indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone \u03b1 promoter by this mutant, suggests that the amphipathic \u03b1-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.<\/jats:p>","DOI":"10.1073\/pnas.94.1.248","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:36:44Z","timestamp":1027679804000},"page":"248-253","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":94,"title":["A natural transactivation mutation in the thyroid hormone  \u03b2 receptor: Impaired interaction with putative transcriptional\u2009mediators"],"prefix":"10.1073","volume":"94","author":[{"given":"T.\u2009N.","family":"Collingwood","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Cambridge, Level 5, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0448; Sahlgren\u2019s University Hospital, University of Gothenburg, S-41345 Gothenburg, Sweden; and Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, Lincoln\u2019s Inn Fields, London WC2A 3PX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O.","family":"Rajanayagam","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Level 5, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0448; Sahlgren\u2019s University Hospital, University of Gothenburg, S-41345 Gothenburg, Sweden; and Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, Lincoln\u2019s Inn Fields, London WC2A 3PX, United 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Hospital, University of Gothenburg, S-41345 Gothenburg, Sweden; and Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, Lincoln\u2019s Inn Fields, London WC2A 3PX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Lindstedt","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Level 5, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0448; Sahlgren\u2019s University Hospital, University of Gothenburg, S-41345 Gothenburg, Sweden; and Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, Lincoln\u2019s Inn Fields, London WC2A 3PX, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Tisell","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Level 5, Addenbrooke\u2019s 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