GPC3-Unc5 receptor complex structure and role in cell migration.
GPC3-Unc5 receptor complex structure and role in cell migration.
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DOI：
10.1016/j.cell.2022.09.025
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发表时间：
2022-10-13
期刊：
影响因子：
64.5
通讯作者：
Seiradake, Elena
中科院分区：
文献类型：
--
作者：
Akkermans, Onno;Delloye-Bourgeois, Celine;Peregrina, Claudia;Carrasquero-Ordaz, Maria;Kokolaki, Maria;Berbeira-Santana, Miguel;Chavent, Matthieu;Reynaud, Florie;Raj, Ritu;Agirre, Jon;Aksu, Metin;White, Eleanor S.;Lowe, Edward;Ben Amar, Dounia;Zaballa, Sofia;Huo, Jiandong;Pakos, Irene;McCubbin, Patrick T. N.;Comoletti, Davide;Owens, Raymond J.;Robinson, Carol V.;Castellani, Valerie;del Toro, Daniel;Seiradake, Elena
神经迁移是大脑发育的关键步骤，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进行传播。在这里，我们揭示了uncoordinate -5受体D （Unc5D）与形态发生受体glypican-3 （GPC3）复合物的晶体结构，形成了一个八聚体糖蛋白复合物。在这个复合体中，四个Unc5D分子排列成一个反平行束，两侧是四个GPC3分子。中心聚糖-聚糖相互作用是由来自GPC3（人类为N241）和Unc5D血栓反应蛋白样结构域的c -甘露糖基化色氨酸的n-链聚糖形成的。MD模拟、质谱分析和基于结构的突变体验证了晶体学数据。抗GPC3纳米体增强或减弱Unc5-GPC3结合，并与突变蛋白一起，表明Unc5/GPC3引导小鼠皮层锥体神经元的迁移，以及胚胎异种移植神经母细胞瘤模型中的癌细胞。结果证明了细胞引导的保守结构机制，其中精细平衡的Unc5-GPC3相互作用调节细胞迁移。抗GPC3纳米体（Nanoglue, nanobreakak）增强或减弱Unc5-GPC3结合Unc5/GPC3信号在体外引起细胞接触排斥。对uncoordination -5 receptor D （Unc5D）和形态原受体glypican-3 （GPC3）结合的详细结构分析和调控揭示了Unc5-GPC3精细平衡的相互作用如何调节神经元和癌细胞的迁移。
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. Uncoordinated-5 receptor D (Unc5D) and glypican-3 (GPC3) form an octameric complex Anti-GPC3 nanobodies (Nanoglue, Nanobreak) enhance or weaken Unc5-GPC3 binding Unc5/GPC3 signaling causes cell contact-repulsion in vitro In vivo, Unc5/GPC3 modulate the migration of cortical neurons and neuroblastoma cells Detailed structural analysis and modulation of binding between uncoordinated-5 receptor D (Unc5D) and morphogen receptor glypican-3 (GPC3) reveal how finely balanced Unc5-GPC3 interactions regulate the migration of neuronal and cancer cells.
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影响因子：
7.8
作者：
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通讯作者：
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Castellani, Valerie
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