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PDBsum entry 1jpw
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Cell adhesion
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PDB id
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1jpw
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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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Structure of a human tcf4-Beta-Catenin complex.
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Authors
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F.Poy,
M.Lepourcelet,
R.A.Shivdasani,
M.J.Eck.
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Ref.
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Nat Struct Biol, 2001,
8,
1053-1057.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
Figure 1. Structure of the Tcf4 -  -catenin
complex. a, The Tcf4 peptide (yellow) has two sites of
interaction with the armadillo repeat region of  -catenin
(blue): an 'extended region' composed of residues 13 -25
(labeled N in yellow) and a more C-terminal helical region
composed of residues 40 -50 (labeled C in yellow). The
intervening 14 residues are disordered, as are residues 8 -12 at
the N-terminus and 51 -54 at the C-terminus. b, Detail of
interactions in the extended region. Tcf4 residues Asp 16 and
Glu 17 form salt bridge hydrogen bonds with -catenin
Lys 435 and Lys 508, respectively. For clarity, only a subset of
the hydrogen bonds in this region is indicated. c, Detail of
interactions in the C-terminal helix. Tcf4 residues Leu 41, Val
44, Leu 48 and Val 49 form the hydrophobic surface of the
amphipathic helix. In (b,c), Tcf4 residues are colored yellow
and -catenin
residues are shown in blue. Thin magenta lines indicate hydrogen
bonds; the small red sphere is an ordered water molecule. The
figure was prepared with MOLSCRIPT33.
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Figure 2.
Figure 2. The Tcf4 extended region binds a positively charged
groove. a, Stereo view of the molecular surface of -catenin,
colored by electrostatic potential, reveals a positively charged
cleft. Acidic residues at either end of the extended portion of
Tcf4 form salt bridges with basic residues in -catenin
(Fig. 1). Leu 18, Ile 19 and Phe 21 form hydrophobic
interactions in the center of the cleft. Electrostatics were
calculated with the peptide removed using GRASP34 and are shaded
from -10 kT e^-1 (red) to +10 kT e^-1 (blue). b, Stereo view of
the 2F[o] - F[c] electron density map corresponding to a segment
of Tcf4, calculated with molecular replacement phases prior to
inclusion of Tcf4 in the model. The 2.8 Å map is contoured at
0.8  and
shown with the final refined Tcf4 model.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2001,
8,
1053-1057)
copyright 2001.
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