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Molecular and Cellular Biology, October 2002, p. 6831-6841, Vol. 22, No. 19
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.19.6831-6841.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Novel Mechanism of Nuclear Receptor Corepressor Interaction Dictated by Activation Function 2 Helix Determinants

Anna N. Moraitis,1,2 Vincent Giguère,1,2,3,4* and Catherine C. Thompson5

Molecular Oncology Group, McGill University Health CenterDepartments of,1 Biochemistry,2 Medicine,3 Oncology, McGill University, Montréal, Québec, Canada,4 Kennedy Krieger Institute, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 212055

Received 16 January 2002/ Returned for modification 5 March 2002/ Accepted 26 June 2002

Transcriptional regulation by nuclear receptors is controlled by the concerted action of coactivator and corepressor proteins. The product of the thyroid hormone-regulated mammalian gene hairless (Hr) was recently shown to function as a thyroid hormone receptor corepressor. Here we report that Hr acts as a potent repressor of transcriptional activation by ROR{alpha}, an orphan nuclear receptor essential for cerebellar development. In contrast to other corepressor-nuclear receptor interactions, Hr binding to ROR{alpha} is mediated by two LXXLL-containing motifs, a mechanism associated with coactivator interaction. Mutagenesis of conserved amino acids in the ligand binding domain indicates that ROR{alpha} activity is ligand-dependent, suggesting that corepressor activity is maintained in the presence of ligand. Despite similar recognition helices shared with coactivators, Hr does not compete for the same molecular determinants at the surface of the ROR{alpha} ligand binding domain, indicating that Hr-mediated repression is not simply through displacement of coactivators. Remarkably, the specificity of Hr corepressor action can be transferred to a retinoic acid receptor by exchanging the activation function 2 (AF-2) helix. Repression of the chimeric receptor is observed in the presence of retinoic acid, demonstrating that in this context, Hr is indeed a ligand-oblivious nuclear receptor corepressor. These results suggest a novel molecular mechanism for corepressor action and demonstrate that the AF-2 helix can play a dynamic role in controlling corepressor as well as coactivator interactions. The interaction of Hr with ROR{alpha} provides direct evidence for the convergence of thyroid hormone and ROR{alpha}-mediated pathways in cerebellar development.

* Corresponding author. Mailing address: Molecular Oncology Group, McGill University Health Center, Room H5-21, 687 Pine Ave. West, Montréal, Québec, Canada H3A 1A1. Phone (514) 843-1406. Fax: (514) 843-1478. E-mail: vgiguere{at}dir.molonc.mcgill.ca.

Molecular and Cellular Biology, October 2002, p. 6831-6841, Vol. 22, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.19.6831-6841.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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