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PDBsum entry 1ijy
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Signaling protein
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PDB id
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1ijy
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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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Insights into wnt binding and signalling from the structures of two frizzled cysteine-Rich domains.
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Authors
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C.E.Dann,
J.C.Hsieh,
A.Rattner,
D.Sharma,
J.Nathans,
D.J.Leahy.
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Ref.
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Nature, 2001,
412,
86-90.
[DOI no: ]
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PubMed id
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Abstract
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Members of the Frizzled family of seven-pass transmembrane proteins serve as
receptors for Wnt signalling proteins. Wnt proteins have important roles in the
differentiation and patterning of diverse tissues during animal development, and
inappropriate activation of Wnt signalling pathways is a key feature of many
cancers. An extracellular cysteine-rich domain (CRD) at the amino terminus of
Frizzled proteins binds Wnt proteins, as do homologous domains in soluble
proteins-termed secreted Frizzled-related proteins-that function as antagonists
of Wnt signalling. Recently, an LDL-receptor-related protein has been shown to
function as a co-receptor for Wnt proteins and to bind to a Frizzled CRD in a
Wnt-dependent manner. To investigate the molecular nature of the Wnt signalling
complex, we determined the crystal structures of the CRDs from mouse Frizzled 8
and secreted Frizzled-related protein 3. Here we show a previously unknown
protein fold, and the design and interpretation of CRD mutations that identify a
Wnt-binding site. CRDs exhibit a conserved dimer interface that may be a feature
of Wnt signalling. This work provides a framework for studies of homologous CRDs
in proteins including muscle-specific kinase and Smoothened, a component of the
Hedgehog signalling pathway.
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Figure 1.
Figure 1: Crystal structure of the sFRP-3 and mFz8 CRDs. a,
Ribbon diagram of the sFRP-3 CRD with elements of secondary
structure numbered in order of appearance in the primary
structure. b, Superposition of sFRP-3 CRD (blue) and mFz8 CRD
(brown). c, Dimer of the sFRP-3 CRD observed in the crystal. d,
Dimer of the mFz8 CRD observed in the crystal. a, c, d,  -helices,
blue; 3[10]-helices, yellow;  -strands,
green; coil, gold. Disulphide bonds are shown as ball-and-stick
models in yellow and black. Images were generated by RIBBONS28.
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Figure 4.
Figure 4: Surfaces involved in Wnt -CRD interactions modelled on
the mFz8 CRD structure. Mutations that do not affect binding
(green), that produce weak binding (orange) and that disrupt
binding (red) are indicated. The orientation of the CRD surface
on the left is identical to the ribbon diagrams in Fig. 1b; the
orientation on the right is rotated 180° about a vertical axis.
a, Locations of the 16 Gly-Ser-Gly (GSG) insertions in the DFz2
CRD that did not affect binding to XWnt8 -AP (green indicates
the two amino acids that flank the point of insertion). b,
Alanine scanning mutations in the mFz8 CRD. Alanine substitution
of residues 117 and 118 (green) in the mFz8 CRD permitted
binding when associated with two alanine substitutions upstream
of this location, but not when associated with two alanine
substitutions downstream. c, Homologue scanning mutations for
mFz6/mFz8 CRD. Deletion of residues 114 -120 in the mFz8 CRD
eliminates binding, but deletion of residues 114 -118 (green)
does not. Images were generated by GRASP30.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2001,
412,
86-90)
copyright 2001.
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