Tcf4 can specifically recognize beta-catenin using alternative conformations

Accumulation of the Wnt pathway effector beta -catenin is a hallmark of a n umber of cancers, including colon cancer. As beta -catenin accumulates in t he cell, it forms a complex with Tcf family transcription factors and activ ates the transcription of several critical genes involved in cell prolifera tion. Because Tcf4 is the predominant Tcf factor present in colon cancer ce lls, drugs that specifically disrupt the beta -catenin-Tcf4 complex could b e useful in treating colon cancers. Earlier structural and biochemical stud ies demonstrated that the central region of the beta -catenin binding domai n of Tcf is essential for anchoring Tcf to beta -catenin Wa two conserved l ysines in beta -catenin (called the charged 'buttons'). Here we report the crystal structure of a beta -catenin-Tcf4 complex at 2.0 Angstrom resolutio n. Our structural and mutagenesis studies show that Tcf4 docks specifically to beta -catenin using several distinct conformations in its essential cen tral region. These conformations allow different glutamate residues in the central region of Tcf4 to form a salt bridge with the same critical charged button, Lys 312 of beta -catenin. We propose that this interaction may be the first event in beta -catenin-Tcf4 recognition.