title: Crystal structures of the extracellular domain of LRP6 and its complex with DKK1.
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.
authors: Department of Biological Structure, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Zhihong
authors: Z
authors: Cheng
authors: Travis
authors: T
authors: Biechele
authors: Zhiyi
authors: Z
authors: Wei
authors: Seamus
authors: S
authors: Morrone
authors: Randall T
authors: RT
authors: Moon
authors: Liguo
authors: L
authors: Wang
authors: Wenqing
authors: W
authors: Xu
mesh_terms: D018360:Crystallography, X-Ray; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D046912:Multiprotein Complexes; D004815:Epidermal Growth Factor