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PDBsum entry 2ic2
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Protein binding
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PDB id
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2ic2
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References listed in PDB file
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Key reference
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Title
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Structure of a heparin-Dependent complex of hedgehog and ihog.
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Authors
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J.S.Mclellan,
S.Yao,
X.Zheng,
B.V.Geisbrecht,
R.Ghirlando,
P.A.Beachy,
D.J.Leahy.
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Ref.
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Proc Natl Acad Sci U S A, 2006,
103,
17208-17213.
[DOI no: ]
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PubMed id
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Abstract
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Hedgehog (Hh) signaling molecules mediate key tissue-patterning events during
animal development, and inappropriate activation of Hh signaling in adults has
been associated with human cancers. Recently, a conserved family of type I
integral membrane proteins required for normal response to the Hh signal was
discovered. One member of this family, Ihog (interference hedgehog), functions
upstream or at the level of Patched (Ptc), but how Ihog participates in Hh
signaling remains unclear. Here, we show that heparin binding induces Ihog
dimerization and is required to mediate high-affinity interactions between Ihog
and Hh. We also present crystal structures of a Hh-binding fragment of Ihog,
both alone and complexed with Hh. Heparin is not well ordered in these
structures, but a basic cleft in the first FNIII domain of Ihog (IhogFn1) is
shown by mutagenesis to mediate heparin binding. These results establish that Hh
directly binds Ihog and provide the first demonstration of a specific role for
heparin in Hh responsiveness.
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Figure 1.
Fig. 1. IhogFn1–2 adopts a horseshoe-like structure. (A)
Ribbon diagram of IhogFn1–2. IhogFn1 is colored green, and
IhogFn2 is colored light blue. A disordered loop is indicated by
the dashed line. (B) An electrostatic potential surface of
IhogFn1–2, shown in the same orientation as in A. The scale is
calibrated to –12 kT/e and +12 kT/e for red and blue,
respectively. Three sulfate ions are shown as orange and red
sticks. All structure images were generated with PyMOL
(http://pymol.sourceforge.net).
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Figure 3.
Fig. 3. HhN binds to a cleft on IhogFn1. (A)
Semitransparent molecular surface of the HhN/IhogFn1–2 complex
superimposed on a ribbon diagram of the molecules. HhN is
colored yellow, IhogFn1 is green, and IhogFn2 is light blue. The
four residues that when mutated lead to loss of heparin binding
are colored dark blue. (B) Electrostatic potential surface of
the HhN/IhogFn1–2 complex, shown in the same orientation as in
A. The black dotted line marks the boundary between HhN and
IhogFn1–2. The four residues that when mutated lead to loss of
heparin binding are outlined with white dashes. The color scale
is calibrated to –12 kT/e and +12 kT/e for red and blue,
respectively. (C) HhN/IhogFn1–2 interface. The four Hh
residues mutated in the HhN/Ihog-interface 1 mutant are
represented as balls and sticks, as are nearby IhogFn1–2
residues. Bridging waters are represented by red spheres and
hydrogen bonds are shown as dashed lines. (D) Effects of
HhN-interface mutations on HhN binding to Ihog-expressing
Drosophila cultured cells.
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