The p160 coactivator PAS-B motif stabilizes nuclear receptor binding and contributes to isoform-specific regulation by Thyroid hormone receptors

Martin L. Privalsky, Sangho Lee, Johnnie B. Hahm, Briana M. Young, Rebecca N G Fong, Ivan H. Chan

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that play multiple roles in vertebrate endocrinology and development. TRs are expressed as a series of distinct receptor isoforms that mediate different biological functions. The TRβ2 isoform is expressed primarily in the hypothalamus, pituitary, cochlea, and retina, and displays an enhanced response to hormone agonist relative to the other TR isoforms. We report here that the unusual transcriptional properties of TRβ2 parallel the ability of this isoform to bind p160 coactivators cooperatively through multiple contact surfaces; the more broadly expressed TRβ1 isoform, in contrast, utilizes a single contact mechanism. Intriguingly, the PAS-B domain in the p160 N terminus plays a previously unanticipated role in permitting TRβ2 to recruit coactivator at limiting triiodothyronine concentrations. The PAS-B sequences also play an important role in coactivator binding by estrogen receptor-α. We propose that the PAS-B domain of the p160 coactivators is an important modulator of coactivator recruitment for a specific subset of nuclear receptors, permitting stronger transcriptional activation at lower hormone concentrations than would otherwise occur, and allowing isoform-specific mRNA splicing to customize the hormone response in different tissues.

Original languageEnglish (US)
Pages (from-to)19554-19563
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number29
DOIs
StatePublished - Jul 17 2009

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Thyroid Hormone Receptors
Cytoplasmic and Nuclear Receptors
Protein Isoforms
Hormones
Endocrinology
RNA Isoforms
Cochlea
Triiodothyronine
Estrogen Receptors
Transcriptional Activation
Hypothalamus
Vertebrates
Retina
Transcription Factors
Modulators
Chemical activation
Tissue
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The p160 coactivator PAS-B motif stabilizes nuclear receptor binding and contributes to isoform-specific regulation by Thyroid hormone receptors. / Privalsky, Martin L.; Lee, Sangho; Hahm, Johnnie B.; Young, Briana M.; Fong, Rebecca N G; Chan, Ivan H.

In: Journal of Biological Chemistry, Vol. 284, No. 29, 17.07.2009, p. 19554-19563.

Research output: Contribution to journalArticle

Privalsky, Martin L. ; Lee, Sangho ; Hahm, Johnnie B. ; Young, Briana M. ; Fong, Rebecca N G ; Chan, Ivan H. / The p160 coactivator PAS-B motif stabilizes nuclear receptor binding and contributes to isoform-specific regulation by Thyroid hormone receptors. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 29. pp. 19554-19563.
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