NDLI: A natural transactivation mutation in the thyroid hormone β receptor: Impaired interaction with putative transcriptional mediators

Content Provider	PubMed Central
Author	Collingwood, T. n. Rajanayagam, O. Adams, M. Wagner, R. Cavaillès, V. Kalkhoven, E. Matthews, C. Nystrom, E. Stenlof, K. Lindstedt, G. Tisell, L. Fletterick, R. j. Parker, M. g. Chatterjee, V. k. k.
Copyright Year	1997
Abstract	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 β receptor (TRβ) 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 α-helix at the carboxyl terminus of TRβ and the position of the homologous residue in the crystal structure of TRα 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 α promoter by this mutant, suggests that the amphipathic α-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.
Starting Page	248
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	1
Volume Number	94
Language	English
Publisher	The National Academy of Sciences of the USA
Publisher Date	1997-01-07
Access Restriction	Open
Rights Holder	The National Academy of Sciences of the USA
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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