Role of retinoid receptor coactivator pockets in cofactor recruitment and transcriptional regulation
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2001-03-29Keywords
Amino Acid MotifsAmino 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
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
J Biol Chem. 2001 Jun 22;276(25):23127-34. Epub 2001 Mar 27. Link to article on publisher's siteDOI
10.1074/jbc.M100462200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42391PubMed ID
11274211Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M100462200