7NDG

Cryo-EM structure of the ternary complex between Netrin-1, Neogenin and Repulsive Guidance Molecule B

Summary for 7NDG

• Entry DOI: 10.2210/pdb7ndg/pdb
• EMDB information: 12286
• Descriptor: Netrin-1, Neogenin, Repulsive Guidance Molecule B (C-terminal region), ... (6 entities in total)
• Functional Keywords: signal transduction, cell surface receptors, neuron regeneration, cell migration, netrin, neogenin, repulsive guidance molecule, complex structure, protein-protein interactions, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 391642.15

Authors

Robinson, R.A.,Griffiths, S.C.,van de Haar, L.L.,Malinauskas, T.,van Battum, E.Y.,Zelina, P.,Schwab, R.A.,Karia, D.,Malinauskaite, L.,Brignani, S.,van den Munkhof, M.,Dudukcu, O.,De Ruiter, A.A.,Van den Heuvel, D.M.A.,Bishop, B.,Elegheert, J.,Aricescu, A.R.,Pasterkamp, R.J.,Siebold, C. (deposition date: 2021-02-01, release date: 2021-03-31, Last modification date: 2024-11-06)

Primary citation

Robinson, R.A.,Griffiths, S.C.,van de Haar, L.L.,Malinauskas, T.,van Battum, E.Y.,Zelina, P.,Schwab, R.A.,Karia, D.,Malinauskaite, L.,Brignani, S.,van den Munkhof, M.H.,Dudukcu, O.,De Ruiter, A.A.,Van den Heuvel, D.M.A.,Bishop, B.,Elegheert, J.,Aricescu, A.R.,Pasterkamp, R.J.,Siebold, C.
Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling.
Cell, 184:2103-, 2021

PubMed 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.

PubMed: 33740419
DOI: 10.1016/j.cell.2021.02.045

Experimental method

ELECTRON MICROSCOPY (5.98 Å)