小柯机器人

英国牛津大学Christian Siebold和荷兰乌得勒支大学R. Jeroen Pasterkamp研究团队合作取得最新进展。他们揭示指导信号Netrin-1（NET1）和排斥性指导分子（RGM）同时结合可阻止细胞外Neogenin（NEO1）信号传导。该项研究成果发表在2021年3月18日出版的《细胞》杂志上。

他们表明信号整合是通过三元NEO1-NET1-RGM复合物的形成而发生的，它会触发下游信号的相互沉默。他们的NEO1-NET1-RGM结构揭示细胞膜上的“三聚体-三聚体”超级复合物。通过防止信号兼容的RGM-NEO1复合物和NET1诱导的NEO1胞外域聚蔟的形成，超级复合物的形成可抑制RGMA-NEO1介导的生长锥塌陷和RGMA-或NET1-NEO1介导的神经元迁移。

这些结果说明了具有相反功能的配体同时结合到单个受体是如何不导致结合竞争的，是因为形成了减少其功能输出的超级复合物。

据悉，在细胞迁移或分化过程中，细胞表面受体同时接触不同的配体。然而，通常不清楚这些细胞外信号如何整合。当NET1配体结合时，NEO1充当吸引性的指导受体，但它通过RGM配体介导排斥。

附：英文原文

Title: Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling

Author: Ross A. Robinson, Samuel C. Griffiths, Lieke L. van de Haar, Tomas Malinauskas, Eljo Y. van Battum, Pavol Zelina, Rebekka A. Schwab, Dimple Karia, Lina Malinauskaite, Sara Brignani, Marleen H. van den Munkhof, zge Düdükcü, Anna A. De Ruiter, Dianne M.A. Van den Heuvel, Benjamin Bishop, Jonathan Elegheert, A. Radu Aricescu, R. Jeroen Pasterkamp, Christian Siebold

Issue&Volume: 2021-03-18

Abstract: During cell migration or differentiation, cell surface receptors are simultaneously exposed to different ligands. However, it is often unclear how these extracellular signals are integrated. Neogenin (NEO1) acts as an attractive guidance receptor when the Netrin-1 (NET1) ligand binds, but it mediates repulsion via repulsive guidance molecule (RGM) ligands. Here, we show that signal integration occurs through the formation of a ternary NEO1-NET1-RGM complex, which triggers reciprocal silencing of downstream signaling. Our NEO1-NET1-RGM structures reveal a “trimer-of-trimers” super-assembly, which exists in the cell membrane. Super-assembly formation results in inhibition of RGMA-NEO1-mediated growth cone collapse and RGMA- or NET1-NEO1-mediated neuron migration, by preventing formation of signaling-compatible RGM-NEO1 complexes and NET1-induced NEO1 ectodomain clustering. These results illustrate how simultaneous binding of ligands with opposing functions, to a single receptor, does not lead to competition for binding, but to formation of a super-complex that diminishes their functional outputs.

DOI: 10.1016/j.cell.2021.02.045

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00234-8