Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6

Dev Cell. 2011 Nov 15;21(5):862-73. doi: 10.1016/j.devcel.2011.09.003. Epub 2011 Oct 13.

Abstract

LDL receptor-related proteins 5 and 6 (LRP5/6) are coreceptors for Wnt growth factors, and also bind Dkk proteins, secreted inhibitors of Wnt signaling. The LRP5/6 ectodomain contains four β-propeller/EGF-like domain repeats. The first two repeats, LRP6(1-2), bind to several Wnt variants, whereas LRP6(3-4) binds other Wnts. We present the crystal structure of the Dkk1 C-terminal domain bound to LRP6(3-4), and show that the Dkk1 N-terminal domain binds to LRP6(1-2), demonstrating that a single Dkk1 molecule can bind to both portions of the LRP6 ectodomain and thereby inhibit different Wnts. Small-angle X-ray scattering analysis of LRP6(1-4) bound to a noninhibitory antibody fragment or to full-length Dkk1 shows that in both cases the ectodomain adopts a curved conformation that places the first three repeats at a similar height relative to the membrane. Thus, Wnts bound to either portion of the LRP6 ectodomain likely bear a similar spatial relationship to Frizzled coreceptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Humans
  • Intercellular Signaling Peptides and Proteins / chemistry
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-5 / chemistry
  • Low Density Lipoprotein Receptor-Related Protein-5 / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-6 / chemistry
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
  • Models, Molecular
  • Protein Conformation
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / chemistry
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway* / drug effects

Substances

  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • LRP5 protein, human
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Wnt Proteins