Crystal structure of a beta-catenin/Tcf complex

The Wnt signaling pathway plays critical roles in embryonic development and tumorigenesis. Stimulation of the Wnt pathway results in the accumulation of a nuclear beta -catenin/Tcf complex, activating Wnt target genes. A crys tal structure of beta -catenin bound to the beta -catenin binding domain of Tcf3 (Tcf3-CBD) has been determined. The Tcf3-CBD forms an elongated struc ture with three binding modules that runs antiparallel to beta -catenin alo ng the positively charged groove formed by the armadillo repeats. Structure -based mutagenesis defines three sites in beta -catenin that are critical f or binding the Tcf3-CBD and are differentially involved in binding APC, cad herin, and Axin. The structural and mutagenesis data reveal a potential tar get for molecular drug design studies.