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Structural Insights into the Inhibition of Wnt Signaling by Cancer Antigen 5T4/Wnt-Activated Inhibitory Factor 1

DOI: 10.1016/j.str.2014.01.009 DOI Help
PMID: 24582434 PMID Help

Authors: Yuguang Zhao (University of Oxford) , Tomas Malinauskas (University of Oxford) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , Edith Jones (Wellcome Trust Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: February 2014
Diamond Proposal Number(s): 8423

Open Access Open Access

Abstract: 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.

Journal Keywords: Conserved; Crystallography; X-Ray; Gene; Gene; Neoplastic; HEK293; Humans; Hydrophobic; Membrane; Models; Molecular; Protein; Secondary; Protein; Tertiary; Proteins; Sequence; Amino; Wnt; beta Catenin

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography

Added On: 05/03/2014 16:19

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