A mechanism for pituitary-resistance to thyroid hormone (PRTH) syndrome: A loss in cooperative coactivator contacts by thyroid hormone receptor (TR)β 2

Sangho Lee, Briana M. Young, Wei Wan, Ivan H. Chan, Martin L. Privalsky

Research output: Contribution to journalArticle

25 Scopus citations

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 TRβ 2 isoform is expressed in the hypothalamus and pituitary, where it plays an important role in the feedback regulation of thyroid hormone levels. TRβ 2 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 TRβ 1 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 TRβ 2 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 TRβ 2 to assume a conformation compatible with its mode of multiple contact coactivator recruitment, whereas disruption of these charge clusters disrupts normal T3 homeostasis by reducing TRβ 2 to a TRβ1-like, single contact mode of coactivator binding.

Original languageEnglish (US)
Pages (from-to)1111-1125
Number of pages15
JournalMolecular Endocrinology
Volume25
Issue number7
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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