Crystal Structure of a β-Catenin/BCL9/Tcf4 Complex

SummaryThe canonical Wnt pathway plays critical roles in embryonic development, stem cell growth, and tumorigenesis. Stimulation of the Wnt pathway leads to the association of β-catenin with Tcf and BCL9 in the nucleus, resulting in the transactivation of Wnt target genes. We have determined the crystal structure of a β-catenin/BCL9/Tcf-4 triple complex at 2.6 Å resolution. Our studies reveal that the β-catenin binding site of BCL9 is distinct from that of most other β-catenin partners and forms a good target for developing drugs that block canonical Wnt/β-catenin signaling. The BCL9 β-catenin binding domain (CBD) forms an α helix that binds to the first armadillo repeat of β-catenin, which can be mutated to prevent β-catenin binding to BCL9 without affecting cadherin or α-catenin binding. We also demonstrate that β-catenin Y142 phosphorylation, which has been proposed to regulate BCL9-2 binding, does not directly affect the interaction of β-catenin with either BCL9 or BCL9-2.