7NDG

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

7NDG の概要

• エントリーDOI: 10.2210/pdb7ndg/pdb
• EMDBエントリー: 12286
• 分子名称: Netrin-1, Neogenin, Repulsive Guidance Molecule B (C-terminal region), ... (6 entities in total)
• 機能のキーワード: signal transduction, cell surface receptors, neuron regeneration, cell migration, netrin, neogenin, repulsive guidance molecule, complex structure, protein-protein interactions, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 391642.15

構造登録者

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. (登録日: 2021-02-01, 公開日: 2021-03-31, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (5.98 Å)