Molecular Endocrinology, Vol 8, 31-39, Copyright © 1994 by Endocrine Society

ARTICLES

Ordered binding of retinoic acid and retinoid-X receptors to asymmetric response elements involves determinants adjacent to the DNA-binding domain

PF Predki, D Zamble, B Sarkar and V Giguere
Division of Biochemistry, Hospital for Sick Children, Toronto, Canada.

Retinoic acid, a pleiotropic regulator of development and homeostasis, controls the expression of specific gene networks via direct interactions with nuclear receptors. The retinoic acid receptor (RAR), as a heterodimer with the retinoid-x receptor (RXR), binds to DNA recognition sites, referred to as retinoic acid response elements (RAREs), that are generally composed of a direct repeat of the half- site core motif PuGGTCA spaced by 2 (DR-2) or 5 (DR-5) basepairs. The asymmetric nature of direct repeat RAREs suggests that RAR and RXR bind preferentially to one of the two half-site core motifs. Here we show that RXR occupies the 5'-up-stream half-site, and RAR the 3'-down- stream half-site of the direct repeat in both DR-2 and DR-5 RAREs. We also demonstrate that a region adjacent to the zinc finger region of RAR and RXR is essential for specific and cooperative binding of DNA- binding domain peptides to RAREs. However, differential utilization of these determinants mediate RAR-RXR heterodimer binding to DR-2 and DR-5 RAREs. The demonstration of ordered but nonequivalent binding of RAR- RXR complexes to DR-2 and DR-5 RAREs sets a precedent for the generation of sequence specificities in heterodimeric DNA-binding proteins.

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