Tcf4 can specifically recognize beta-catenin using alternative conformations.
Accumulation of the Wnt pathway effector beta-catenin is a hallmark of a number of cancers, including colon cancer. As beta-catenin accumulates in the cell, it forms a complex with Tcf family transcription factors and activates the transcription of several critical genes involved in cell proliferation. Because Tcf4 is the predominant Tcf factor present in colon cancer cells, drugs that specifically disrupt the beta-catenin-Tcf4 complex could be useful in treating colon cancers. Earlier structural and biochemical studies demonstrated that the central region of the beta-catenin binding domain of Tcf is essential for anchoring Tcf to beta-catenin via two conserved lysines in beta-catenin (called the charged 'buttons'). Here we report the crystal structure of a beta-catenin-Tcf4 complex at 2.0 A resolution. Our structural and mutagenesis studies show that Tcf4 docks specifically to beta-catenin using several distinct conformations in its essential central 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.
Graham
T A
TA
Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
Ferkey
D M
DM
Mao
F
F
Kimelman
D
D
Xu
W
W
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D024002:HMGB Proteins; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011233:Precipitin Tests; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics; D055672:Static Electricity; D013379:Substrate Specificity; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D029867:Xenopus Proteins / Q000737:chemistry / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D024002:HMGB Proteins; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D029867:Xenopus Proteins; D051176:beta Catenin; C544896:tcf7l2 protein, Xenopus; D018698:Glutamic Acid; D008239:Lysine