Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling
Cell. 2021-04-01; 184(8): 2103-2120.e31
DOI: 10.1016/j.cell.2021.02.045
Lire sur PubMed
1. Cell. 2021 Apr 15;184(8):2103-2120.e31. doi: 10.1016/j.cell.2021.02.045. Epub
2021 Mar 18.
Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1
signaling.
Robinson RA(1), Griffiths SC(1), van de Haar LL(2), Malinauskas T(1), van Battum
EY(2), Zelina P(2), Schwab RA(1), Karia D(1), Malinauskaite L(3), Brignani S(2),
van den Munkhof MH(2), Düdükcü Ö(2), De Ruiter AA(2), Van den Heuvel DMA(2),
Bishop B(1), Elegheert J(1), Aricescu AR(4), Pasterkamp RJ(5), Siebold C(6).
Author information:
(1)Division of Structural Biology, Wellcome Centre for Human Genetics,
University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
(2)Department of Translational Neuroscience, UMC Utrecht Brain Center,
University Medical Center, Utrecht University, Universiteitsweg 100, 3584 CG
Utrecht, the Netherlands.
(3)MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis
Crick Avenue, Cambridge CB2 0QH, UK.
(4)Division of Structural Biology, Wellcome Centre for Human Genetics,
University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; MRC Laboratory of
Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge
CB2 0QH, UK.
(5)Department of Translational Neuroscience, UMC Utrecht Brain Center,
University Medical Center, Utrecht University, Universiteitsweg 100, 3584 CG
Utrecht, the Netherlands. Electronic address: .
(6)Division of Structural Biology, Wellcome Centre for Human Genetics,
University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. Electronic address:
.
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.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2021.02.045
PMCID: PMC8063088
PMID: 33740419 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors declare no
competing interests.