Abstract
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.
Original language | English (US) |
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Article number | e2217096120 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 120 |
Issue number | 20 |
DOIs | |
State | Published - 2023 |
Keywords
- Wnt signaling
- X-ray structure
- extracellular domain
- lipid-binding protein
- negative feedback regulation
ASJC Scopus subject areas
- General