Robinson Ross A, Griffiths Samuel C, van de Haar Lieke L, Malinauskas Tomas, van Battum Eljo Y, Zelina Pavol, Schwab Rebekka A, Karia Dimple, Malinauskaite Lina, Brignani Sara, van den Munkhof Marleen H, Düdükcü Özge, De Ruiter Anna A, Van den Heuvel Dianne M A, Bishop Benjamin, Elegheert Jonathan, Aricescu A Radu, Pasterkamp R Jeroen, Siebold Christian
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
Cell. 2021 Apr 15;184(8):2103-2120.e31. doi: 10.1016/j.cell.2021.02.045. Epub 2021 Mar 18.
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.
在细胞迁移或分化过程中，细胞表面受体同时暴露于不同的配体。然而，这些细胞外信号是如何整合的往往并不清楚。当Netrin-1（NET1）配体结合时，新生蛋白（NEO1）作为一种吸引性导向受体发挥作用，但它通过排斥性导向分子（RGM）配体介导排斥作用。在这里，我们表明信号整合通过三元NEO1-NET1-RGM复合物的形成而发生，该复合物触发下游信号的相互沉默。我们的NEO1-NET1-RGM结构揭示了一种存在于细胞膜中的“三聚体三聚体”超级组装体。超级组装体的形成通过阻止信号兼容的RGM-NEO1复合物的形成以及NET1诱导的NEO1胞外域聚集，从而抑制RGMA-NEO1介导的生长锥塌陷以及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与单个受体同时结合时，如何不会导致结合竞争，而是形成一个减少其功能输出的超级复合物。
