title: A mechanism for pituitary-resistance to thyroid hormone (PRTH) syndrome: a loss in cooperative coactivator contacts by thyroid hormone receptor (TR)beta2.
abstract: Thyroid hormone receptors (TR) are hormone-modulated transcription factors that regulate overall metabolic rate, lipid utilization, heart rate, and development. TR are expressed as a mix of interrelated receptor isoforms. The TRβ2 isoform is expressed in the hypothalamus and pituitary, where it plays an important role in the feedback regulation of thyroid hormone levels. TRβ2 exhibits unique transcriptional properties that parallel the ability of this isoform to bind to certain coactivators cooperatively through multiple contact surfaces. The more peripherally expressed TRβ1 isoform, in contrast, appears to recruit these coactivators through a single contact mechanism. We report here that clusters of charged amino acids in the TR hormone-binding domain are required for this enhanced mode of coactivator recruitment and that mutations in these charge clusters, by disrupting TRβ2 coactivator binding, are a molecular basis for pituitary resistance to thyroid hormone, a disease characterized by inappropriate thyroid hormone feedback regulation. We propose that the charge clusters allow wild-type TRβ2 to assume a conformation compatible with its mode of multiple contact coactivator recruitment, whereas disruption of these charge clusters disrupts normal T(3) homeostasis by reducing TRβ2 to a TRβ1-like, single contact mode of coactivator binding.
authors.affiliation: Department of Microbiology, College of Biological Sciences, University of California at Davis, Davis, California 95616, USA.
authors.forename: Sangho
authors.initials: S
authors.lastname: Lee
authors.forename: Briana M
authors.initials: BM
authors.lastname: Young
authors.forename: Wei
authors.initials: W
authors.lastname: Wan
authors.forename: Ivan H
authors.initials: IH
authors.lastname: Chan
authors.forename: Martin L
authors.initials: ML
authors.lastname: Privalsky
mesh_terms: D020816:Amino Acid Motifs; D001120:Arginine / Q000737:chemistry; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D020125:Mutation, Missense; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D020218:Response Elements; D013499:Surface Properties; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D055767:Immobilized Proteins; D020033:Protein Isoforms; D037042:Thyroid Hormone Receptors beta; D001120:Arginine; D008156:Luciferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1