期刊
STRUCTURE
卷 22, 期 4, 页码 612-620出版社
CELL PRESS
DOI: 10.1016/j.str.2014.01.009
关键词
-
资金
- Cancer Research UK
- UK Medical Research Council [A10976, G9900061]
- Wellcome Trust [090532/Z/09/Z]
- BioStruct-X project
- European Commission
- UK Medical Research Council
- Cancer Research UK [17721, 10976] Funding Source: researchfish
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/beta-catenin signaling, a signaling system central to many developmental and pathological processes. Wnt/beta-catenin signaling is controlled by multiple inhibitors and activators. Here, we report crystal structures for the extracellular domain of 5T4/WAIF1 at 1.8 angstrom 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/beta-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/beta-catenin signaling.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据