7ndg

Publication Abstract from PubMed

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.

Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling.,Robinson RA, Griffiths SC, van de Haar LL, Malinauskas T, van Battum EY, Zelina P, Schwab RA, Karia D, Malinauskaite L, Brignani S, van den Munkhof MH, Dudukcu O, De Ruiter AA, Van den Heuvel DMA, Bishop B, Elegheert J, Aricescu AR, Pasterkamp RJ, Siebold C Cell. 2021 Apr 15;184(8):2103-2120.e31. doi: 10.1016/j.cell.2021.02.045. Epub , 2021 Mar 18. PMID:33740419^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.