ICAT Inhibits beta-Catenin Binding to Tcf/Lef-Family Transcription Factors and in the General Coactivator p300 Using Independent Structural Modules
- SLAC
In the canonical Wnt signaling pathway, {beta}-catenin activates target genes through its interactions with Tcf/Lef-family transcription factors and additional transcriptional coactivators. The crystal structure of ICAT, an inhibitor of {beta}-catenin-mediated transcription, bound to the armadillo repeat domain of {beta}-catenin, has been determined. ICAT contains an N-terminal helilical domain that binds to repeats 11 and 12 of {beta}-catenin, and an extended C-terminal region that binds to repeats 5-10 in a manner similar that of Tcfs and other {beta}-catenin ligands. Full-length ICAT dissociates complexes of {beta}-catenin, Lef-1, and the transcriptional coactivator p300, whereas the helical domain alone selectively blocks binding to p300. The C-terminal armadillo repeats of {beta}-catenin may be an attractive target for compounds designed to disrupt aberrant {beta}-catenin-mediated transcription associated with various cancers.
- Research Organization:
- Stanford Linear Accelerator Center, Menlo Park, CA (US); Stanford Synchrotron Radiation Lab. (US)
- Sponsoring Organization:
- USDOE Office of Science (US)
- DOE Contract Number:
- AC03-76SF00515
- OSTI ID:
- 815849
- Report Number(s):
- SLAC-REPRINT-2002-254
- Journal Information:
- Molecular Cell, Journal Name: Molecular Cell
- Country of Publication:
- United States
- Language:
- English
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