Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling
| Autor: | Christian Siebold, Eljo Y. van Battum, Rebekka A. Schwab, Lina Malinauskaite, R.A. Robinson, A. Radu Aricescu, Pavol Zelina, B. Bishop, Marleen H. van den Munkhof, R. Jeroen Pasterkamp, O. Dudukcu, Lieke L. van de Haar, Tomas Malinauskas, Jonathan Elegheert, Sara Brignani, S.C. Griffiths, Dianne M.A. van den Heuvel, Anna A. De Ruiter, D. Karia |
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| Přispěvatelé: | Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Předmět: |
cell migration
protein-protein interactions Cell membrane morphogen signaling Mice 0302 clinical medicine repulsive guidance molecule Cell Movement Lateral Ventricles Netrin RNA Small Interfering ComputingMilieux_MISCELLANEOUS Mice Knockout Neurons Oncogene Proteins 0303 health sciences Cell migration DCC Receptor medicine.anatomical_structure Ectodomain RNA Interference Signal transduction signal transduction Protein Binding Cell Adhesion Molecules Neuronal Growth Cones Nerve Tissue Proteins Biology GPI-Linked Proteins General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Cell surface receptor medicine Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Protein Structure Quaternary 030304 developmental biology Neogenin cell surface receptors axon regeneration Repulsive guidance molecule Mice Inbred C57BL complex structure Biophysics Axon guidance Protein Multimerization 030217 neurology & neurosurgery |
| Zdroj: | Cell Cell, Elsevier, 2021, 184 (8), pp.2103-2120.e31. ⟨10.1016/j.cell.2021.02.045⟩ |
| ISSN: | 0092-8674 1097-4172 |
| DOI: | 10.1016/j.cell.2021.02.045 |
| Popis: | Summary 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. Graphical abstract Highlights • The NEO1-NET1 structure suggests NET1-mediated NEO1/DCC cell surface clustering • The receptor NEO1 and its ligands NET1 and RGM form a trimer-of-trimers supercomplex • NET1 inhibits RGMA-induced growth cone collapse via the NEO1-NET1-RGM complex • The NEO1-NET1-RGM complex silences RGM and NET1 effects on neuron migration When extracellular guidance molecules Netrin and RGM that have opposing functions simultaneously bind the Neogenin receptor, a super-complex is formed that diminishes their functional outputs. |
| Databáze: | OpenAIRE |
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