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PDBsum entry 1th1
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Cell adhesion/antitumor protein
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PDB id
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1th1
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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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Crystal structure of a beta-Catenin/apc complex reveals a critical role for apc phosphorylation in apc function.
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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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Ref.
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Mol Cell, 2004,
15,
523-533.
[DOI no: ]
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PubMed id
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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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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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