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

Fu Lien Hsieh, Tao Hsin Chang, Sandra B. Gabelli, Jeremy Nathans

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Article numbere2217096120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number20
DOIs
StatePublished - 2023

Keywords

  • Wnt signaling
  • X-ray structure
  • extracellular domain
  • lipid-binding protein
  • negative feedback regulation

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein'. Together they form a unique fingerprint.

Cite this