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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.

Original publication

DOI

10.1016/j.str.2014.01.009

Type

Journal article

Journal

Structure

Publication Date

08/04/2014

Volume

22

Pages

612 - 620

Keywords

Amino Acid Sequence, Conserved Sequence, Crystallography, X-Ray, Gene Expression, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Membrane Glycoproteins, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Proteins, Sequence Homology, Amino Acid, Wnt Signaling Pathway, beta Catenin