Title

Interactions that determine the assembly of a retinoid X receptor/corepressor complex

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Department of Cancer Biology

Publication Date

4-25-2002

Document Type

Article

Subjects

Amino Acid Sequence; Binding Sites; Cell Line; Cell Nucleus; DNA; DNA-Binding Proteins; Dimerization; Glutathione Transferase; Humans; Models, Genetic; Models, Molecular; Molecular Sequence Data; Mutation; Plasmids; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Repressor Proteins; Retinoid X Receptors; Sequence Homology, Amino Acid; Transcription Factors; Transcription, Genetic; Transfection

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

The retinoid X receptor (RXR) is a key regulator in multiple signaling pathways because it can form either a homodimer with itself or a heterodimer with members of the class I nuclear receptors. The RXR-containing dimers regulate transcription by recruiting coactivators or corepressors to the target promoters. The binding of coactivators to RXR is mediated through a hydrophobic pocket formed in part by the C-terminal activation helix (AF-2). However, little is known about interactions of corepressors with RXR and its roles in transcriptional repression. Here we show that the repression activity of RXR correlates with its binding to the corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT). This intrinsic repression activity is masked by the AF-2 helix, which antagonizes SMRT binding. Inhibition of SMRT binding by the AF-2 helix requires specific amino acid sequences and the helical structure. Furthermore, the SMRT-binding site on RXR is independent of helix 11 but overlaps with the coactivator-binding pocket. On the basis of these results, we propose a structural model to help understand the molecular mechanism of corepressor recruitment by RXR.

Rights and Permissions

Citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):5842-7. Epub 2002 Apr 23. Link to article on publisher's site

DOI of Published Version

10.1073/pnas.092043399

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID

11972046