Structure of a human Tcf4-beta-catenin complex.
The multifunctional protein beta-catenin is important for cell adhesion, because it binds cadherins, and the Wnt signal transduction pathway, where it interacts with the Adenomatous polyposis coli (APC) protein and TCF/Lef family transcription factors. Mutations in APC or in beta-catenin are estimated to trigger formation of over 90% of all colon cancers. In colonic epithelia, these mutations produce elevated levels of Tcf4-beta-catenin, which stimulates a transcriptional response that initiates polyp formation and eventually malignant growth. Thus, disruption of the Tcf4-beta-catenin interaction may be an attractive goal for therapeutic intervention. Here we describe the crystal structure of a human Tcf4-beta-catenin complex and compare it with recent structures of beta-catenin in complex with Xenopus Tcf3 (XTcf3) and mammalian E-cadherin. The structure reveals anticipated similarities with the closely related XTcf3 complex but unexpectedly lacks one component observed in the XTcf3 structure.
Poy
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Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Lepourcelet
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Shivdasani
R A
RA
Eck
M J
MJ
D000818:Animals; D001665:Binding Sites; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D017930:Genes, Reporter / Q000235:genetics; D024002:HMGB Proteins; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D020449:Repetitive Sequences, Amino Acid; D055672:Static Electricity; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D029867:Xenopus Proteins / Q000737:chemistry / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; 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