The structural basis of DKK-mediated inhibition of Wnt/LRP signaling

Abstract

Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) mediate canonical Wnt-β-catenin signaling by forming a complex with the co-receptor Frizzled, which binds to Wnt proteins. Dickkopf (DKK)-related proteins inhibit the Wnt signaling pathway by directly binding to the ectodomains of LRP5/6. However, the mechanism for DKK-mediated antagonism has not been fully understood as of yet. Crystal structures of the LRP6 ectodomain in complex with DKK1, along with mutagenesis studies, provide considerable insights into the molecular basis for DKK-mediated inhibition and Wnt signaling through LRP5/6.

Fig. 1

Schematic representation of the domains of full-length LRP6, with the locations of the HBM mutations and the domains that interact with different ligands indicated. LDLR, low-density lipoprotein receptor.

Fig. 2

(A) Molecular mechanism of inhibition of Wnt signaling by DKK1C. The binding site of DKK1C partially overlaps with that of Wnt3a on LRP6 P3P4. DKK1C is shown in cartoon representation, and LRP6 P3E3P4E4 is shown in surface representation. Residues of LRP6 P3E3P4 involved in both DKK1C and Wnt3a binding are shown in blue; residues of LRP6 P3P4 that interact only with Wnt3a are shown in yellow. Residues of DKK1C that directly compete with Wnt3a for binding on LRP6 P3E3P4E4 are shown in stick representation (including Glu¹⁸⁵, His²⁰⁴, Phe²⁰⁵, Trp²⁰⁶, Leu²³¹, and Ile²³³; for simplicity, the labels of these residues are not shown). The atomic coordinates are from Protein Data Bank accession no. 3S8V. The Wnt3a binding surface is adopted from Chen et al. (27). (B) Proposed mechanism of the DKK1-LRP6 ECD interaction. All four β propellers of LRP6 ECD are shown in surface representation. DKK1 (including the N-terminal peptide and DKK1C) is shown in cartoon representation. Selected HBM mutations are indicated.