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PDBsum entry 3soq
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Protein binding/antagonist
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PDB id
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3soq
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References listed in PDB file
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Key reference
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Title
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Wnt antagonists bind through a short peptide to the first β-Propeller domain of lrp5/6.
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Authors
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E.Bourhis,
W.Wang,
C.Tam,
J.Hwang,
Y.Zhang,
D.Spittler,
O.W.Huang,
Y.Gong,
A.Estevez,
I.Zilberleyb,
L.Rouge,
C.Chiu,
Y.Wu,
M.Costa,
R.N.Hannoush,
Y.Franke,
A.G.Cochran.
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Ref.
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Structure, 2011,
19,
1433-1442.
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PubMed id
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Abstract
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The Wnt pathway inhibitors DKK1 and sclerostin (SOST) are important therapeutic
targets in diseases involving bone loss or damage. It has been appreciated that
Wnt coreceptors LRP5/6 are also important, as human missense mutations that
result in bone overgrowth (bone mineral density, or BMD, mutations) cluster to
the E1 propeller domain of LRP5. Here, we report a crystal structure of LRP6 E1
bound to an antibody, revealing that the E1 domain is a peptide recognition
module. Remarkably, the consensus E1 binding sequence is a close match to a
conserved tripeptide motif present in all Wnt inhibitors that bind LRP5/6. We
show that this motif is important for DKK1 and SOST binding to LRP6 and for
inhibitory function, providing a detailed structural explanation for the effect
of the BMD mutations.
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