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* Residue conservation analysis
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Enzyme class:
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Chains A, D, B, E, C, F:
E.C.?
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DOI no:
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Nat Struct Biol
8:1053-1057
(2001)
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PubMed id:
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Structure of a human Tcf4-beta-catenin complex.
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F.Poy,
M.Lepourcelet,
R.A.Shivdasani,
M.J.Eck.
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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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Selected figure(s)
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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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Figures were
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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R.Lu,
F.Bian,
X.Zhang,
H.Qi,
E.Y.Chuang,
S.C.Pflugfelder,
and
D.Q.Li
(2011).
The β-catenin/Tcf4/survivin signaling maintains a less differentiated phenotype and high proliferative capacity of human corneal epithelial progenitor cells.
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Int J Biochem Cell Biol,
43,
751-759.
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S.Mokhtarzada,
C.Yu,
A.Brickenden,
and
W.Y.Choy
(2011).
Structural characterization of partially disordered human chibby: insights into its function in the wnt-signaling pathway.
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Biochemistry,
50,
715-726.
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G.S.Yochum,
C.M.Sherrick,
M.Macpartlin,
and
R.H.Goodman
(2010).
A beta-catenin/TCF-coordinated chromatin loop at MYC integrates 5' and 3' Wnt responsive enhancers.
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Proc Natl Acad Sci U S A,
107,
145-150.
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O.Hansson,
Y.Zhou,
E.Renström,
and
P.Osmark
(2010).
Molecular function of TCF7L2: Consequences of TCF7L2 splicing for molecular function and risk for type 2 diabetes.
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Curr Diab Rep,
10,
444-451.
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P.M.Evans,
X.Chen,
W.Zhang,
and
C.Liu
(2010).
KLF4 interacts with beta-catenin/TCF4 and blocks p300/CBP recruitment by beta-catenin.
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Mol Cell Biol,
30,
372-381.
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J.Liu,
B.T.Phillips,
M.F.Amaya,
J.Kimble,
and
W.Xu
(2008).
The C. elegans SYS-1 protein is a bona fide beta-catenin.
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Dev Cell,
14,
751-761.
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PDB codes:
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L.Jin,
Y.Li,
C.J.Chen,
M.A.Sherman,
K.Le,
and
J.E.Shively
(2008).
Direct interaction of tumor suppressor CEACAM1 with beta catenin: identification of key residues in the long cytoplasmic domain.
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Exp Biol Med (Maywood),
233,
849-859.
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M.Iiizumi,
W.Liu,
S.K.Pai,
E.Furuta,
and
K.Watabe
(2008).
Drug development against metastasis-related genes and their pathways: a rationale for cancer therapy.
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Biochim Biophys Acta,
1786,
87.
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D.Sinner,
J.J.Kordich,
J.R.Spence,
R.Opoka,
S.Rankin,
S.C.Lin,
D.Jonatan,
A.M.Zorn,
and
J.M.Wells
(2007).
Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells.
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Mol Cell Biol,
27,
7802-7815.
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M.J.Gorczynski,
J.Grembecka,
Y.Zhou,
Y.Kong,
L.Roudaia,
M.G.Douvas,
M.Newman,
I.Bielnicka,
G.Baber,
T.Corpora,
J.Shi,
M.Sridharan,
R.Lilien,
B.R.Donald,
N.A.Speck,
M.L.Brown,
and
J.H.Bushweller
(2007).
Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta.
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Chem Biol,
14,
1186-1197.
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M.Ritco-Vonsovici,
A.Ababou,
and
M.Horton
(2007).
Molecular plasticity of beta-catenin: new insights from single-molecule measurements and MD simulation.
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Protein Sci,
16,
1984-1998.
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E.Oksanen,
V.P.Jaakola,
T.Tolonen,
K.Valkonen,
B.Akerström,
N.Kalkkinen,
V.Virtanen,
and
A.Goldman
(2006).
Reindeer beta-lactoglobulin crystal structure with pseudo-body-centred noncrystallographic symmetry.
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Acta Crystallogr D Biol Crystallogr,
62,
1369-1374.
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PDB code:
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F.Tang,
Y.Peng,
J.J.Nau,
E.J.Kauffman,
and
L.S.Weisman
(2006).
Vac8p, an armadillo repeat protein, coordinates vacuole inheritance with multiple vacuolar processes.
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Traffic,
7,
1368-1377.
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H.J.Choi,
A.H.Huber,
and
W.I.Weis
(2006).
Thermodynamics of beta-catenin-ligand interactions: the roles of the N- and C-terminal tails in modulating binding affinity.
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J Biol Chem,
281,
1027-1038.
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J.Sampietro,
C.L.Dahlberg,
U.S.Cho,
T.R.Hinds,
D.Kimelman,
and
W.Xu
(2006).
Crystal structure of a beta-catenin/BCL9/Tcf4 complex.
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Mol Cell,
24,
293-300.
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PDB code:
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J.Y.Trosset,
C.Dalvit,
S.Knapp,
M.Fasolini,
M.Veronesi,
S.Mantegani,
L.M.Gianellini,
C.Catana,
M.Sundström,
P.F.Stouten,
and
J.K.Moll
(2006).
Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening.
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Proteins,
64,
60-67.
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N.Janssens,
M.Janicot,
and
T.Perera
(2006).
The Wnt-dependent signaling pathways as target in oncology drug discovery.
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Invest New Drugs,
24,
263-280.
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S.Takayama,
I.Rogatsky,
L.E.Schwarcz,
and
B.D.Darimont
(2006).
The glucocorticoid receptor represses cyclin D1 by targeting the Tcf-beta-catenin complex.
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J Biol Chem,
281,
17856-17863.
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D.L.Daniels,
and
W.I.Weis
(2005).
Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation.
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Nat Struct Mol Biol,
12,
364-371.
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R.Gail,
R.Frank,
and
A.Wittinghofer
(2005).
Systematic peptide array-based delineation of the differential beta-catenin interaction with Tcf4, E-cadherin, and adenomatous polyposis coli.
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J Biol Chem,
280,
7107-7117.
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J.M.Gooding,
K.L.Yap,
and
M.Ikura
(2004).
The cadherin-catenin complex as a focal point of cell adhesion and signalling: new insights from three-dimensional structures.
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Bioessays,
26,
497-511.
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K.H.Emami,
C.Nguyen,
H.Ma,
D.H.Kim,
K.W.Jeong,
M.Eguchi,
R.T.Moon,
J.L.Teo,
S.W.Oh,
H.Y.Kim,
S.H.Moon,
J.R.Ha,
and
M.Kahn
(2004).
A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected].
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Proc Natl Acad Sci U S A,
101,
12682-12687.
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L.Lévy,
Y.Wei,
C.Labalette,
Y.Wu,
C.A.Renard,
M.A.Buendia,
and
C.Neuveut
(2004).
Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction.
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Mol Cell Biol,
24,
3404-3414.
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M.Lepourcelet,
Y.N.Chen,
D.S.France,
H.Wang,
P.Crews,
F.Petersen,
C.Bruseo,
A.W.Wood,
and
R.A.Shivdasani
(2004).
Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex.
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Cancer Cell,
5,
91.
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Y.Xing,
W.K.Clements,
I.Le Trong,
T.R.Hinds,
R.Stenkamp,
D.Kimelman,
and
W.Xu
(2004).
Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.
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Mol Cell,
15,
523-533.
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PDB code:
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A.L.Amir,
M.Barua,
N.C.McKnight,
S.Cheng,
X.Yuan,
and
S.P.Balk
(2003).
A direct beta-catenin-independent interaction between androgen receptor and T cell factor 4.
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J Biol Chem,
278,
30828-30834.
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T.Pawson,
and
P.Nash
(2003).
Assembly of cell regulatory systems through protein interaction domains.
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Science,
300,
445-452.
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A.Hurlstone,
and
H.Clevers
(2002).
T-cell factors: turn-ons and turn-offs.
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EMBO J,
21,
2303-2311.
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H.J.Dyson,
and
P.E.Wright
(2002).
Coupling of folding and binding for unstructured proteins.
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Curr Opin Struct Biol,
12,
54-60.
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M.van de Wetering,
W.de Lau,
and
H.Clevers
(2002).
WNT signaling and lymphocyte development.
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Cell,
109,
S13-S19.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
