Crystal structure of a beta-catenin/BCL9/Tcf4 complex.
The canonical Wnt pathway plays critical roles in embryonic development, stem cell growth, and tumorigenesis. Stimulation of the Wnt pathway leads to the association of beta-catenin with Tcf and BCL9 in the nucleus, resulting in the transactivation of Wnt target genes. We have determined the crystal structure of a beta-catenin/BCL9/Tcf-4 triple complex at 2.6 A resolution. Our studies reveal that the beta-catenin binding site of BCL9 is distinct from that of most other beta-catenin partners and forms a good target for developing drugs that block canonical Wnt/beta-catenin signaling. The BCL9 beta-catenin binding domain (CBD) forms an alpha helix that binds to the first armadillo repeat of beta-catenin, which can be mutated to prevent beta-catenin binding to BCL9 without affecting cadherin or alpha-catenin binding. We also demonstrate that beta-catenin Y142 phosphorylation, which has been proposed to regulate BCL9-2 binding, does not directly affect the interaction of beta-catenin with either BCL9 or BCL9-2.
Sampietro
James
J
Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
Dahlberg
Caroline L
CL
Cho
Uhn Soo
US
Hinds
Thomas R
TR
Kimelman
David
D
Xu
Wenqing
W
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry*; D011487:Protein Conformation; D051820:TCF Transcription Factors / Q000737:chemistry*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D015533:Transcriptional Activation; D014981:Xenopus; D029867:Xenopus Proteins; D051178:alpha Catenin / Q000737:chemistry; D051176:beta Catenin / Q000737:chemistry*
C111180:BCL9 protein, human; D009363:Neoplasm Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D029867:Xenopus Proteins; D051178:alpha Catenin; D051176:beta Catenin; C544896:tcf7l2 protein, Xenopus