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

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.

• Authors: Fu-Lien Hsieh, Tao-Hsin Chang, Sandra B Gabelli, Jeremy Nathans
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 120 Issue 20 Pg. e2217096120 (05 16 2023) ISSN: 1091-6490 [Electronic] United States
• PMID: 37155902 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

• Humans
• Membrane Proteins (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Wnt Signaling Pathway
• Adenomatous Polyposis Coli
• Lipids
• beta Catenin (genetics, metabolism)