Cryo-EM structure of human Wntless in complex with Wnt3a

Area of Science:

• Structural Biology
• Molecular Biology
• Biochemistry

Background:

• Wntless (WLS) is vital for secreting Wnt proteins, which regulate critical cellular processes.
• Dysregulated Wnt signaling is linked to various human diseases, notably cancers.

Purpose of the Study:

• To determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human WLS in complex with Wnt3a.
• To elucidate the molecular mechanisms underlying Wnt palmitoleoylation and secretion mediated by WLS.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to resolve the structure of the WLS-Wnt3a complex.
• Analysis of protein-protein interactions and structural features at 2.2 Å resolution.

Main Results:

• The transmembrane domain of WLS exhibits a GPCR fold with a central cavity and lateral opening.
• Wnt3a binds WLS via multiple interfaces, with its lipid moiety entering a hydrophobic tunnel in the WLS transmembrane domain.
• A Wnt3a β-hairpin, containing the palmitoleoylation site, extensively interacts with WLS, proving essential for Wnt secretion.

Conclusions:

• The study provides unprecedented structural insights into the Wnt secretion process.
• Understanding WLS-Wnt3a interactions illuminates the mechanism of Wnt palmitoleoylation and secretion.
• These findings are crucial for comprehending Wnt signaling in health and disease, particularly in cancer.