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PDBsum entry 4cnm
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Cell adhesion
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PDB id
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4cnm
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References listed in PDB file
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Key reference
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Title
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Structural insights into the inhibition of wnt signaling by cancer antigen 5t4/wnt-Activated inhibitory factor 1.
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Authors
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Y.Zhao,
T.Malinauskas,
K.Harlos,
E.Y.Jones.
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Ref.
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Structure, 2014,
22,
612-620.
[DOI no: ]
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PubMed id
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Abstract
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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.
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