Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein

Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2217096120. doi: 10.1073/pnas.2217096120. Epub 2023 May 8.


Diverse extracellular proteins negatively regulate WNT signaling. One such regulator is adenomatosis polyposis coli down-regulated 1 (APCDD1), a conserved single-span transmembrane protein. In response to WNT signaling in a variety of tissues, APCDD1 transcripts are highly up-regulated. We have determined the three-dimensional structure of the extracellular domain of APCDD1, and this structure reveals an unusual architecture consisting of two closely apposed β-barrel domains (ABD1 and ABD2). ABD2, but not ABD1, has a large hydrophobic pocket that accommodates a bound lipid. The APCDD1 ECD can also bind to WNT7A, presumably via its covalently bound palmitoleate, a modification that is common to all WNTs and is essential for signaling. This work suggests that APCDD1 functions as a negative feedback regulator by titrating WNT ligands at the surface of responding cells.

Keywords: Wnt signaling; X-ray structure; extracellular domain; lipid-binding protein; negative feedback regulation.

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

  • Adenomatous Polyposis Coli*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipids
  • Membrane Proteins* / metabolism
  • Wnt Signaling Pathway
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Membrane Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lipids
  • beta Catenin
  • APCDD1 protein, human