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* Residue conservation analysis
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PDB id:
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Cell adhesion/antitumor protein
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Title:
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Beta-catenin in complex with a phosphorylated apc 20aa repeat fragment
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Structure:
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Beta-catenin. Chain: a, b. Fragment: armadillo repeat. Synonym: pro2286. Engineered: yes. Adenomatous polyposis coli protein. Chain: c, d. Fragment: phosphorylated 20 amino acid repeat. Synonym: apc protein.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ctnnb1, ctnnb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: apc, dp2.5. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Biol. unit:
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Dimer (from
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Resolution:
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2.50Å
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R-factor:
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0.225
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R-free:
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0.257
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Authors:
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Y.Xing,W.K.Clements,I.Le Trong,T.R.Hinds,R.Stenkamp,D.Kimelman,W.Xu
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Key ref:
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Y.Xing
et al.
(2004).
Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.
Mol Cell,
15,
523-533.
PubMed id:
DOI:
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Date:
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31-May-04
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Release date:
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07-Sep-04
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PROCHECK
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Headers
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References
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DOI no:
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Mol Cell
15:523-533
(2004)
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PubMed id:
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Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.
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Y.Xing,
W.K.Clements,
I.Le Trong,
T.R.Hinds,
R.Stenkamp,
D.Kimelman,
W.Xu.
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ABSTRACT
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The tumor suppressor adenomatous polyposis coli (APC) plays a critical role in
the turnover of cytosolic beta-catenin, the key effector of the canonical Wnt
signaling pathway. APC contains seven 20 amino acid (20 aa) beta-catenin binding
repeats that are required for beta-catenin turnover. We have determined the
crystal structure of beta-catenin in complex with a phosphorylated APC fragment
containing two 20 aa repeats. Surprisingly, one single phosphorylated 20 aa
repeat, together with its flanking regions, covers the entire structural groove
of beta-catenin and may thus compete for beta-catenin binding with all other
beta-catenin armadillo repeat partners. Our biochemical studies show that
phosphorylation of the APC 20 aa repeats increases the affinity of the repeats
for beta-catenin by 300- to 500-fold and the phosphorylated 20 aa repeats
prevent beta-catenin binding to Tcf. Our work suggests that the phosphorylation
of the APC 20 aa repeats could be a critical switch for APC function.
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Selected figure(s)
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Figure 2.
Figure 2. Interactions between the Extended Region of
Phospho-APC and β-Catenin(A) Electrostatic surface of
β-catenin (armadillo repeats 10-12) bound to the α-helix of
APC-2,3 (shown in stick form) N-terminal to the extended region.
The surface of β-catenin is colored according to its relative
electrostatic potential with blue representing positively
charged residues and red representing negatively charged
residues. β-catenin and APC amino acids are labeled in yellow
and red, respectively.(B) Electrostatic surface of β-catenin
(armadillo repeats 5-9) bound to the extended region of
phospho-APC.(C) Critical contacts in the interface between the
phospho-APC extended region and the β-catenin groove of
armadillo repeats 5-9. APC is shown in a red ball-and-stick
representation with red labels, and β-catenin (with helices
colored as in Figure 1B) side chains are yellow with black
labels. Phosphorylated Thr1487 of APC is labeled in italics. The
hydrogen bonding and charge-charge interactions are designated
with pink lines. Water molecules in the interface are shown as
blue balls. For clarity, hydrogen bonds bridged by water
molecules between APC and β-catenin residues, R474, R386, D390,
and K354, are not shown.
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Figure 3.
Figure 3. Interactions between the Third Phospho-20 aa
Repeat of APC and β-Catenin(A) Stereo 2Fo - Fc simulated
annealed omit map of the phosphorylated third 20 aa repeat of
APC (labeled in red) bound to β-catenin. The map is contoured
at 1σ.(B) Electrostatic surface of β-catenin (armadillo
repeats 1-5) bound to the phosphorylated third 20 aa repeat and
its C-terminal residues. APC and β-catenin are colored as in
Figure 2A.(C) Critical contacts in the interface of the
phospho-20 aa repeat of APC bound to the β-catenin groove
formed by armadillo repeats 1-5. APC and β-catenin are colored
as in Figure 2C.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2004,
15,
523-533)
copyright 2004.
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Figures were
selected
by an automated process.
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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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G.Drechsel,
J.Bergler,
K.Wippel,
N.Sauer,
K.Vogelmann,
and
S.Hoth
(2011).
C-terminal armadillo repeats are essential and sufficient for association of the plant U-box armadillo E3 ubiquitin ligase SAUL1 with the plasma membrane.
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J Exp Bot,
62,
775-785.
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A.Venerando,
O.Marin,
G.Cozza,
V.H.Bustos,
S.Sarno,
and
L.A.Pinna
(2010).
Isoform specific phosphorylation of p53 by protein kinase CK1.
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Cell Mol Life Sci,
67,
1105-1118.
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E.M.Kohler,
K.Brauburger,
J.Behrens,
and
J.Schneikert
(2010).
Contribution of the 15 amino acid repeats of truncated APC to beta-catenin degradation and selection of APC mutations in colorectal tumours from FAP patients.
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Oncogene,
29,
1663-1671.
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M.Adamska,
C.Larroux,
M.Adamski,
K.Green,
E.Lovas,
D.Koop,
G.S.Richards,
C.Zwafink,
and
B.M.Degnan
(2010).
Structure and expression of conserved Wnt pathway components in the demosponge Amphimedon queenslandica.
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Evol Dev,
12,
494-518.
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M.M.Rosenberg,
F.Yang,
J.L.Mohn,
E.K.Storer,
and
M.H.Jacob
(2010).
The postsynaptic adenomatous polyposis coli (APC) multiprotein complex is required for localizing neuroligin and neurexin to neuronal nicotinic synapses in vivo.
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J Neurosci,
30,
11073-11085.
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C.Y.Ou,
J.H.Kim,
C.K.Yang,
and
M.R.Stallcup
(2009).
Requirement of Cell Cycle and Apoptosis Regulator 1 for Target Gene Activation by Wnt and {beta}-Catenin and for Anchorage-independent Growth of Human Colon Carcinoma Cells.
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J Biol Chem,
284,
20629-20637.
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K.L.Neufeld
(2009).
Nuclear APC.
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Adv Exp Med Biol,
656,
13-29.
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R.Mo,
T.L.Chew,
M.T.Maher,
G.Bellipanni,
E.S.Weinberg,
and
C.J.Gottardi
(2009).
The terminal region of beta-catenin promotes stability by shielding the Armadillo repeats from the axin-scaffold destruction complex.
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J Biol Chem,
284,
28222-28231.
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W.Zhang,
J.Yang,
Y.Liu,
X.Chen,
T.Yu,
J.Jia,
and
C.Liu
(2009).
PR55 alpha, a regulatory subunit of PP2A, specifically regulates PP2A-mediated beta-catenin dephosphorylation.
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J Biol Chem,
284,
22649-22656.
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B.M.McCartney,
and
I.S.Näthke
(2008).
Cell regulation by the Apc protein Apc as master regulator of epithelia.
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Curr Opin Cell Biol,
20,
186-193.
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E.M.Kohler,
A.Derungs,
G.Daum,
J.Behrens,
and
J.Schneikert
(2008).
Functional definition of the mutation cluster region of adenomatous polyposis coli in colorectal tumours.
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Hum Mol Genet,
17,
1978-1987.
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|
|
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P.R.Rao,
K.Makhijani,
and
L.S.Shashidhara
(2008).
Human APC sequesters beta-catenin even in the absence of GSK-3beta in a Drosophila model.
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Oncogene,
27,
2488-2493.
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X.Chen,
J.Yang,
P.M.Evans,
and
C.Liu
(2008).
Wnt signaling: the good and the bad.
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Acta Biochim Biophys Sin (Shanghai),
40,
577-594.
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Y.Su,
C.Fu,
S.Ishikawa,
A.Stella,
M.Kojima,
K.Shitoh,
E.M.Schreiber,
B.W.Day,
and
B.Liu
(2008).
APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase.
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Mol Cell,
32,
652-661.
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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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D.Kimelman,
and
W.Xu
(2006).
beta-catenin destruction complex: insights and questions from a structural perspective.
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Oncogene,
25,
7482-7491.
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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.Sierra,
T.Yoshida,
C.A.Joazeiro,
and
K.A.Jones
(2006).
The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes.
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Genes Dev,
20,
586-600.
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J.Yang,
W.Zhang,
P.M.Evans,
X.Chen,
X.He,
and
C.Liu
(2006).
Adenomatous polyposis coli (APC) differentially regulates beta-catenin phosphorylation and ubiquitination in colon cancer cells.
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J Biol Chem,
281,
17751-17757.
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N.Barker,
and
H.Clevers
(2006).
Mining the Wnt pathway for cancer therapeutics.
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Nat Rev Drug Discov,
5,
997.
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M.Bienz
(2005).
beta-Catenin: a pivot between cell adhesion and Wnt signalling.
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Curr Biol,
15,
R64-R67.
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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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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
code is
shown on the right.
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Links
