英国牛津大学Elena Seiradake等研究人员合作揭示GPC3-Unc5受体复合物结构和在细胞迁移中的作用。2022年10月13日，国际知名学术期刊《细胞》发表了这一成果。
研究人员揭示了无序-5受体D（Unc5D）与形态发生受体glypican-3（GPC3）复合物的晶体结构，其形成一个八聚体的糖蛋白复合物。在该复合物中，四个Unc5D分子包成一个反平行的束，侧边是四个GPC3分子。中心聚糖-聚糖的相互作用是由来自GPC3的N-连接聚糖（人类为N241），和Unc5D血栓软骨素样结构域的C-甘露糖基化的色氨酸形成的。
MD模拟、质谱分析和基于结构的突变体验证了晶体学数据。GPC3纳米抗体增强或减弱了Unc5-GPC3的结合，并与突变体蛋白一起显示，Unc5/GPC3引导小鼠皮层中迁移的锥体神经元，以及胚胎异种神经母细胞瘤模型中的癌细胞。这些结果证明了一种保守的细胞引导结构机制，其中精细平衡的Unc5-GPC3相互作用调节细胞迁移。
据介绍，神经迁移是大脑发育过程中的一个关键步骤，需要细胞表面引导受体的相互作用。癌细胞经常劫持这些机制来进行传播。
附：英文原文
Title: GPC3-Unc5 receptor complex structure and role in cell migration
Author: Onno Akkermans, Céline Delloye-Bourgeois, Claudia Peregrina, Maria Carrasquero-Ordaz, Maria Kokolaki, Miguel Berbeira-Santana, Matthieu Chavent, Florie Reynaud, Ritu Raj, Jon Agirre, Metin Aksu, Eleanor S. White, Edward Lowe, Dounia Ben Amar, Sofia Zaballa, Jiandong Huo, Irene Pakos, Patrick T.N. McCubbin, Davide Comoletti, Raymond J. Owens, Carol V. Robinson, Valérie Castellani, Daniel del Toro, Elena Seiradake
Issue&Volume: 2022/10/13
Abstract: Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.
DOI: 10.1016/j.cell.2022.09.025
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01197-7