Structural basis of coactivation of liver receptor homolog-1 by β-catenin

We report the three-dimensional structure of a beta-catenin armadillo repeat in complex with the liver receptor homolog-1 (LRH-1) ligand binding domain at 2.8 angstrom resolution as the first structure of beta-catenin in complex with any nuclear receptor. The surface of beta-catenin that binds LRH-1 partly overlaps defined contact sites for peptide segments of beta-catenin partners, including T-cell factor-4. The surface of LRH-1 that engages beta-catenin is comprised of helices 1, 9, and 10 and is distinct from known interaction surfaces of LRH-1, including corepressor and coactivator binding sites. Targeted mutagenesis of amino acids forming both sides of the LRH-1/beta-catenin interface reveals that they are essential for stable interactions between these proteins in solution. The LRH-1 binding site in beta-catenin is also required for association with androgen receptor, providing evidence that the observed LRH-1/beta-catenin interaction may be prototypic.