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

Martin L Privalsky1, Sangho Lee, Johnnie B Hahm

  • 1Department of Microbiology, College of Biological Sciences, University of California, Davis, California 95616, USA. mlprivalsky@ucdavis.edu

The Journal of Biological Chemistry
|June 3, 2009
PubMed

Insights

Thyroid hormone receptors (TRs) have distinct isoforms like TRbeta2 that bind coactivators differently. This isoform-specific binding allows customized hormone responses in various tissues.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Thyroid hormone receptors (TRs) are crucial transcription factors regulating vertebrate development and endocrinology.
  • TRs exist as distinct isoforms, each mediating unique biological functions.
  • The TRbeta2 isoform, found in specific tissues, shows a heightened response to hormone agonists compared to other TRs.

Purpose of the Study:

  • To investigate the molecular mechanisms behind the enhanced transcriptional activity of the TRbeta2 isoform.
  • To elucidate the role of p160 coactivators in mediating TRbeta2 function.
  • To understand how isoform-specific coactivator binding influences hormone response.

Main Methods:

  • Comparative analysis of TRbeta1 and TRbeta2 isoform interactions with p160 coactivators.
  • Investigation of the role of the PAS-B domain in coactivator recruitment.
  • Assessing transcriptional activity at varying hormone concentrations.

Main Results:

  • TRbeta2 binds p160 coactivators cooperatively via multiple contact surfaces, unlike TRbeta1's single contact mechanism.
  • The PAS-B domain of p160 is critical for TRbeta2 coactivator recruitment, especially at low hormone levels.
  • PAS-B domain also influences coactivator binding for estrogen receptor-alpha.

Conclusions:

  • The cooperative binding mechanism of TRbeta2 with p160 coactivators explains its enhanced transcriptional properties.
  • The PAS-B domain acts as a key modulator for coactivator recruitment in specific nuclear receptors, enabling greater activation at lower hormone concentrations.
  • Isoform-specific coactivator binding allows for tissue-specific customization of thyroid hormone responses through mRNA splicing.

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