5UN5

Frizzled-8 complex with designed surrogate Wnt agonist, crystal form 1

5UN5 の概要

• エントリーDOI: 10.2210/pdb5un5/pdb
• 関連するPDBエントリー: 5UN6
• 分子名称: Frizzled-8, Designed Wnt agonist B12 (3 entities in total)
• 機能のキーワード: signaling protein, signaling protein-de novo protein complex, signaling protein/de novo protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Membrane; Multi-pass membrane protein: Q9H461
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 57572.24

構造登録者

Janda, C.Y.,Garcia, K.C. (登録日: 2017-01-30, 公開日: 2017-05-03, 最終更新日: 2024-10-09)

主引用文献

Janda, C.Y.,Dang, L.T.,You, C.,Chang, J.,de Lau, W.,Zhong, Z.A.,Yan, K.S.,Marecic, O.,Siepe, D.,Li, X.,Moody, J.D.,Williams, B.O.,Clevers, H.,Piehler, J.,Baker, D.,Kuo, C.J.,Garcia, K.C.
Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling.
Nature, 545:234-237, 2017

PubMed Abstract: Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

PubMed: 28467818
DOI: 10.1038/nature22306

実験手法

X-RAY DIFFRACTION (2.994 Å)