The p160 coactivator PAS-B motif stabilizes nuclear receptor binding and contributes to isoform-specific regulation by thyroid hormone receptors.
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 TRbeta2 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 TRbeta2 parallel the ability of this isoform to bind p160 coactivators cooperatively through multiple contact surfaces; the more broadly expressed TRbeta1 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 TRbeta2 to recruit coactivator at limiting triiodothyronine concentrations. The PAS-B sequences also play an important role in coactivator binding by estrogen receptor-alpha. 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.
Privalsky
Martin L
ML
Department of Microbiology, College of Biological Sciences, University of California, Davis, California 95616, USA. mlprivalsky@ucdavis.edu
Lee
Sangho
S
Hahm
Johnnie B
JB
Young
Briana M
BM
Fong
Rebecca N G
RN
Chan
Ivan H
IH
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001717:Birds; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology
D047628:Estrogen Receptor alpha; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D014284:Triiodothyronine; D004958:Estradiol; D005982:Glutathione Transferase