The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT.
Beta-catenin is a multifunctional protein involved in both cell adhesion and transcriptional activation. Transcription mediated by the beta-catenin/Tcf complex is involved in embryological development and is upregulated in various cancers. We have determined the crystal structure at 2.5 A resolution of a complex between beta-catenin and ICAT, a protein that prevents the interaction between beta-catenin and Tcf/Lef family transcription factors. ICAT contains a 3-helix bundle that binds armadillo repeats 10-12 and a C-terminal tail that, similar to Tcf and E-cadherin, binds in the groove formed by armadillo repeats 5-9 of beta-catenin. We show that ICAT selectively inhibits beta-catenin/Tcf binding in vivo, without disrupting beta-catenin/cadherin interactions. Thus, it should be possible to design cancer therapeutics that inhibit beta-catenin-mediated transcriptional activation without interfering with cell adhesion.
Graham
Thomas A
TA
Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
Clements
Wilson K
WK
Kimelman
David
D
Xu
Wenqing
W
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008958:Models, Molecular; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology; D029961:Zebrafish Proteins; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; C411982:CTNNBIP1 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin