title: Distinct dimerization domains provide antagonist pathways for thyroid hormone receptor action.
abstract: Transcriptional regulation by thyroid hormone is mediated through its nuclear receptors, which bind to target response elements as homodimers or as heterodimers with proteins such as retinoid X receptors (RXR). Thyroid hormone response elements exhibit remarkable flexibility in that the receptor binding half-sites can be arranged as direct repeats, inverted repeats, or everted repeats. We report that a limited region at the carboxyl-terminal end of the thyroid hormone receptor differentially contributes to the formation of receptor homo- and heterodimers. The functionally inactive thyroid hormone receptor splicing variant alpha 2, which is altered at the juncture of the homo- and heterodimerization domains, cannot form homodimers. However, alpha 2 can form a heterodimer when bound to half-sites arranged as a direct repeat spaced by 4 base pairs (DR4), but not with other arrangements of response element half-sites. The alpha 2-RXR heterodimer strongly inhibits wild type receptor function mediated by the DR4 element, suggesting that the alpha 2 isoform modulates thyroid hormone action by binding as an antagonist to a subset of response elements.
authors.affiliation: Thyroid Unit, Massachusetts General Hospital, Boston.
authors.forename: T
authors.initials: T
authors.lastname: Nagaya
authors.forename: J L
authors.initials: JL
authors.lastname: Jameson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001704:Biopolymers; D008969:Molecular Sequence Data; D009154:Mutation; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D017386:Sequence Homology, Amino Acid
chemical_list: D001704:Biopolymers; D011988:Receptors, Thyroid Hormone