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

Area of Science:

• Molecular Biology
• Cell Signaling
• Structural Biology

Background:

• Extracellular proteins play a crucial role in modulating WNT signaling pathways.
• Adenomatosis polyposis coli down-regulated 1 (APCDD1) is a transmembrane protein known to negatively regulate WNT signaling.
• APCDD1 expression is induced by WNT signaling across various tissues.

Purpose of the Study:

• To elucidate the three-dimensional structure of the extracellular domain (ECD) of APCDD1.
• To investigate the molecular mechanisms by which APCDD1 interacts with WNT ligands.
• To understand the role of APCDD1 in WNT signaling regulation.

Main Methods:

• Three-dimensional structural determination of the APCDD1 ECD using X-ray crystallography or cryo-EM.
• Biochemical assays to assess the binding of APCDD1 to WNT7A.
• Lipid-binding studies to characterize the hydrophobic pocket in APCDD1.

Main Results:

• The APCDD1 ECD exhibits an atypical structure composed of two adjacent beta-barrel domains (ABD1 and ABD2).
• A significant hydrophobic pocket was identified within ABD2, capable of binding a lipid molecule.
• APCDD1 was shown to bind WNT7A, likely mediated by its palmitoleate modification, a critical feature for WNT signaling.

Conclusions:

• APCDD1's unique structure facilitates interaction with WNT ligands.
• The bound lipid in APCDD1 may mediate WNT binding, essential for signaling.
• APCDD1 functions as a negative feedback mechanism by sequestering WNT ligands at the cell surface.