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PDBsum entry 2jtk
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Signaling protein
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PDB id
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2jtk
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References listed in PDB file
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Key reference
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Title
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Structural insight into the mechanisms of wnt signaling antagonism by dkk.
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Authors
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L.Chen,
K.Wang,
Y.Shao,
J.Huang,
X.Li,
J.Shan,
D.Wu,
J.J.Zheng.
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Ref.
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J Biol Chem, 2008,
283,
23364-23370.
[DOI no: ]
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PubMed id
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Abstract
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Dickkopf (Dkk) proteins are antagonists of the canonical Wnt signaling pathway
and are crucial for embryonic cell fate and bone formation. Wnt antagonism of
Dkk requires the binding of the C-terminal cysteine-rich domain of Dkk to the
Wnt coreceptor, LRP5/6. However, the structural basis of the interaction between
Dkk and low density lipoprotein receptor-related protein (LRP) 5/6 is unknown.
In this study, we examined the structure of the Dkk functional domain and
elucidated its interactions with LRP5/6. Using NMR spectroscopy, we determined
the solution structure of the C-terminal cysteine-rich domain of mouse Dkk2
(Dkk2C). Then, guided by mutagenesis studies, we docked Dkk2C to the YWTD
beta-propeller domains of LRP5/6 and showed that the ligand binding site of the
third LRP5/6 beta-propeller domain matches Dkk2C best, suggesting that this
domain binds to Dkk2C with higher affinity. Such differential binding affinity
is likely to play an essential role in Dkk function in the canonical Wnt pathway.
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Figure 2.
FIGURE 2. Solution structure of Dkk2C. A, amino acid
sequence alignment of C-terminal cysteine-rich domains of Dkks
in mouse (m), human (h), Xenopus (x), rabbit (r), and zebrafish
(z).β strand elements identified in the three-dimensional
structure of Dkk2C are indicated at the top. Ten conserved
cysteines are in bold type, and pairs of cysteines forming
disulfide bridges are colored identically and linked by lines.
Amino acids that contact the third β-propeller domain of LRP5
in the docked model are in bold and indicated by the red dots.
B, stereo view of the peptide backbone (N, C-  , C')
determined by superimposition of 20 conformers of Dkk2C with the
lowest target function values. The figure was generated by using
MOLMOL (39). β strands are red; disulfide bridges are yellow.
C, ribbon diagram of Dkk2C with the lowest target function
values, generated by using MOLSCRIPT (40).
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Figure 5.
FIGURE 5. Complex structure of the third β-propeller
domain of LRP5 (LRP5-PD3) bound to Dkk2C. A, a ribbon diagram of
the complex of LRP5-PD3 bound to Dkk2C. B, side chain
interactions between Dkk2C and LRP5-PD3. Dashed lines represent
hydrogen bonds. Residue numbers in brackets are the numbers in
mouse Dkk1. Corresponding amino acids in LRP5-PD1 and LRP5-PD2
to those involved in LRP5-PD3 binding interface are listed in
the right bottom panel. Figures were generated by using the
Pymol program (DeLano Scientific).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
23364-23370)
copyright 2008.
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