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Molecular and Cellular Biology, September 1999, p. 6448-6457, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Novel Role for Helix 12 of Retinoid X Receptor in Regulating Repression

Jinsong Zhang,1,2 Xiao Hu,1 and Mitchell A. Lazar1,3,4,*

Departments of Medicine,1 Biochemistry,2 and Genetics3 and The Penn Diabetes Center,4 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Received 7 May 1999/Returned for modification 21 June 1999/Accepted 24 June 1999

Nutrients, drugs, and hormones influence transcription during differentiation and metabolism by binding to high-affinity nuclear receptors. In the absence of ligand, some but not all nuclear receptors repress transcription as a heterodimer with retinoid X receptor (RXR). Here we define a novel role for helix 12 (H12) in sterically masking the corepressor (CoR) binding site in apo-RXR. Removing H12 converts RXR to a potent transcriptional repressor. The length but not the specific sequence of H12 is critical for masking RXR's intrinsic repression function. This contrasts with the amphipathic character required for mediating ligand-dependent activation and coactivator recruitment. Physiologically, we show that heterodimerization of RXR with apo-thyroid hormone receptor (TR) unmasks the CoR binding site in RXR and allows the TR-RXR heterodimer to repress. A molecular mechanism that involves sequence-specific interaction between RXR H12 and the coactivator-binding surface of the nuclear receptor is proposed for this heterodimerization-mediated unmasking. Peroxisome proliferator-activated receptor gamma  does not interact as well with RXR H12, thus explaining its inability to repress transcription as an RXR heterodimer. The requirement to unmask RXR's latent repression function explains why only certain RXR partners repress transcription.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, 611 CRB, 415 Curie Blvd., Philadelphia, PA 19104-6149. Phone: (215) 898-0198. Fax: (215) 898-5408. E-mail: lazar{at}mail.med.upenn.edu.

Molecular and Cellular Biology, September 1999, p. 6448-6457, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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