Title

Role of retinoid receptor coactivator pockets in cofactor recruitment and transcriptional regulation

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

3-29-2001

Document Type

Article

Subjects

Amino Acid Motifs; Amino Acid Sequence; Base Sequence; DNA Primers; Dimerization; *Gene Expression Regulation; Molecular Sequence Data; Mutagenesis, Site-Directed; Receptors, Retinoic Acid; Sequence Homology, Amino Acid; Trans-Activators; *Transcription Factors; *Transcription, Genetic

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

The nuclear receptor for retinoic acid (RAR) forms a heterodimeric complex with the retinoid X receptor (RXR). This RXR/RAR heterodimer binds to the promoter of retinoic acid target genes and recruits coactivators and corepressors to regulate gene expression. Currently, the relative role of each receptor monomer in regulating coactivator and corepressor recruitment remains unclear. Here we show that the receptor-associated coactivator 3 (RAC3) uses two separate LXXLL motifs to bind RAR and RXR. The mutation of the coactivator-binding pockets of RAR and RXR abolishes RAC3 binding. Although the coactivator pocket of RXR is essential for the function of the RXR homodimer, it has a minor role for the recruitment of RAC3 and trans-activation by the RXR/RAR heterodimer. Consistently, deletion of the activation helix of RXR enhances binding of RAC3 to the heterodimer, and mutation of the coactivator pocket of RXR had little effect on RXR/RAR activity. In contrast, the coactivator pocket and the activation helix of RAR are absolutely required. We also show that different residues of the RAR coactivator pocket are used differently for interactions with the corepressor silencing mediator for retinoid and thyroid hormone receptor (SMRT) and coactivator. These results indicate a differential role for each retinoid receptor to the overall binding of cofactors and regulation of transcription by the retinoid receptor heterodimer.

Rights and Permissions

Citation: J Biol Chem. 2001 Jun 22;276(25):23127-34. Epub 2001 Mar 27. Link to article on publisher's site

DOI of Published Version

10.1074/jbc.M100462200

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of biological chemistry

PubMed ID

11274211