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PDBsum entry 1m1e
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Structural protein
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PDB id
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1m1e
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Icat inhibits beta-Catenin binding to tcf/lef-Family transcription factors and the general coactivator p300 using independent structural modules.
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Authors
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D.L.Daniels,
W.I.Weis.
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Ref.
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Mol Cell, 2002,
10,
573-584.
[DOI no: ]
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PubMed id
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Abstract
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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 to
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.
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Figure 2.
Figure 2. The ICAT Helical Domain(A) Structure of the
helical domain showing key hydrophobic core packing
interactions. Helices A, B, and C are indicated.(B) Hydrophobic
interactions between helix A and residues of β-catenin. The
color scheme is the same as Figure 1B, with β-catenin arm
repeats 11 and 12 termed R11 and R12, respectively. Side chains
from each protein that participate in hydrophobic interactions
are shown. Also shown is the superposition of the region II
helix of E-cadherin (Huber and Weis, 2001) (yellow; residue
numbers shown in parentheses). The superposition was performed
as described in Figure 1C. The hydrogen bond between Tyr 654 of
β-catenin and Asp 665 of E-cadherin is shown with a solid
line.(C) Electrostatic interactions (dashed lines) of ICAT
glutamate residues 37, 38, and 39 with arginine residues in
β-catenin or within ICAT, labeled as in (B). Mutation of these
three residues to alanine abolishes ICAT binding to β-catenin.
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Figure 5.
Figure 5. Model of ICAT as a Bipartite Transcriptional
InhibitorOn the left, transcription activation complexes
consisting of β-catenin, Tcf/Lef, and CBP/p300 are bound to
cognate DNA sites through interaction of the Tcf/Lef HMG box.
Binding of ICAT to β-catenin simultaneously displaces CBP/p300
and Tcf/Lef, allowing for Groucho/TLE repressor proteins to bind
to Tcf/Lef.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2002,
10,
573-584)
copyright 2002.
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