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

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

doi:10.1073/pnas.2217096120

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

Journal Article · 08 May 2023 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.2217096120 · OSTI ID:1972877

Hsieh, Fu-Lien ^[1];

^[1];

^[1]

Johns Hopkins University School of Medicine, Baltimore, MD (United States)

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.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Human Science Frontier Program Organization Fellowship; USDOE

Grant/Contract Number:: SC0012704; R01EY018637; R01CA204345; LT000130/2017-L; P41GM111244; KP1605010; KC0401040

OSTI ID:: 1972877

Alternate ID(s):: OSTI ID: 2425505

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 120, Issue 20; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
science & technology
WNT signaling
negative feedback regulation
extracellular domain
lipid-binding protein
X-ray structure
biological sciences
biophysics and computational biology

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

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