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Nat Struct Mol Biol. 2011 Oct 9;18(11):1204-10. doi: 10.1038/nsmb.2139.

Crystal structures of the extracellular domain of LRP6 and its complex with DKK1.

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1
Department of Biological Structure, University of Washington School of Medicine, Seattle, Washington, USA.

Abstract

Low-density-lipoprotein (LDL) receptor-related proteins 5 and 6 (LRP5/6) are Wnt co-receptors essential for Wnt/β-catenin signaling. Dickkopf 1 (DKK1) inhibits Wnt signaling by interacting with the extracellular domains of LRP5/6 and is a drug target for multiple diseases. Here we present the crystal structures of a human LRP6-E3E4-DKK1 complex and the first and second halves of human LRP6's four propeller-epidermal growth factor (EGF) pairs (LRP6-E1E2 and LRP6-E3E4). Combined with EM analysis, these data demonstrate that LRP6-E1E2 and LRP6-E3E4 form two rigid structural blocks, with a short intervening hinge that restrains their relative orientation. The C-terminal domain of DKK1 (DKK1c) interacts with the top surface of the LRP6-E3 YWTD propeller and given their structural similarity, probably also that of the LRP6-E1 propeller, through conserved hydrophobic patches buttressed by a network of salt bridges and hydrogen bonds. Our work provides key insights for understanding LRP5/6 structure and the interaction of LRP5/6 with DKK, as well as for drug discovery.

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PMID:
21984209
PMCID:
PMC3249237
DOI:
10.1038/nsmb.2139
[Indexed for MEDLINE]
Free PMC Article
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