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Crystal structures of the extracellular domain of LRP6 and its complex with DKK1
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Crystal structures of the extracellular domain of LRP6 and its complex with DKK1
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Crystal structures of the extracellular domain of LRP6 and its complex with DKK1
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Journal Article
Crystal structures of the extracellular domain of LRP6 and its complex with DKK1
2011
Overview
LRP5/6 is a Wnt co-receptor essential for Wnt/β-catenin signaling. X-ray crystallography and electron microscopy analyses now reveal that the LRP6 extracellular ligand-binding domain is composed of two pairs of rigid blocks connected by a short hinge. The structure of the LRP6–DKK1c complex also shows how DKK1 may potently inhibit Wnt/β-catenin signaling through its binding to these structural blocks.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 631/337
/ Biomedical and Life Sciences
/ Cellular signal transduction
/ Epidermal Growth Factor - chemistry
/ Epidermal Growth Factor - genetics
/ Epidermal Growth Factor - metabolism
/ Humans
/ Intercellular Signaling Peptides and Proteins - chemistry
/ Intercellular Signaling Peptides and Proteins - metabolism
/ Low Density Lipoprotein Receptor-Related Protein-6 - chemistry
/ Low Density Lipoprotein Receptor-Related Protein-6 - metabolism
