Structural insights into the inhibition of Wnt signaling by cancer antigen 5T4/Wnt-activated inhibitory factor 1.

Journal article

The tumor antigen 5T4/WAIF1 (Wnt-activated inhibitory factor 1; also known as Trophoblast glycoprotein TPBG) is a cell surface protein targeted in multiple cancer immunotherapy clinical trials. Recently, it has been shown that 5T4/WAIF1 inhibits Wnt/β-catenin signaling, a signaling system central to many developmental and pathological processes. Wnt/β-catenin signaling is controlled by multiple inhibitors and activators. Here, we report crystal structures for the extracellular domain of 5T4/WAIF1 at 1.8 Å resolution. They reveal a highly glycosylated, rigid core, comprising eight leucine-rich repeats (LRRs), which serves as a platform to present evolutionarily conserved surface residues in the N-terminal LRR1. Structural and cell-based analyses, coupled with previously reported in vivo data, suggest that Tyr325 plus the LRR1 surface centered on a second exposed aromatic residue, Phe97, are essential for inhibition of Wnt/β-catenin signaling. These results provide a structural basis for the development of 5T4/WAIF1-targeted therapies that preserve or block 5T4/WAIF1-mediated inhibition of Wnt/β-catenin signaling.

Authors: Zhao, Y; Malinauskas, T; Harlos, K; Jones, E

• Publication status: Published
• Journal: Structure (London, England : 1993)
• Volume: 22
• Issue: 4
• Pages: 612-620
• Publication date: 2014-04-01
• DOI: 10.1016/j.str.2014.01.009
• EISSN: 1878-4186
• ISSN: 0969-2126
• Language: English
• Keywords: Membrane Glycoproteins; Humans; HEK293 Cells; Models, Molecular; Amino Acid Sequence; Wnt Signaling Pathway; Sequence Homology, Amino Acid; Protein Structure, Tertiary; beta Catenin; Hydrophobic and Hydrophilic Interactions; Proteins; Gene Expression; Protein Structure, Secondary; Protein Binding; Conserved Sequence; Crystallography, X-Ray; Gene Expression Regulation, Neoplastic; Molecular Sequence Data