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Neuron. 2014 Aug 20;83(4):839-849. doi: 10.1016/j.neuron.2014.07.010. Epub 2014 Aug 7.

The crystal structure of netrin-1 in complex with DCC reveals the bifunctionality of netrin-1 as a guidance cue.

Author information

1
State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China.
2
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. 02215, USA.
3
European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, 22607, Hamburg, Germany.
4
PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
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Contributed equally

Abstract

Netrin-1 is a guidance cue that can trigger either attraction or repulsion effects on migrating axons of neurons, depending on the repertoire of receptors available on the growth cone. How a single chemotropic molecule can act in such contradictory ways has long been a puzzle at the molecular level. Here we present the crystal structure of netrin-1 in complex with the Deleted in Colorectal Cancer (DCC) receptor. We show that one netrin-1 molecule can simultaneously bind to two DCC molecules through a DCC-specific site and through a unique generic receptor binding site, where sulfate ions staple together positively charged patches on both DCC and netrin-1. Furthermore, we demonstrate that UNC5A can replace DCC on the generic receptor binding site to switch the response from attraction to repulsion. We propose that the modularity of binding allows for the association of other netrin receptors at the generic binding site, eliciting alternative turning responses.

PMID:
25123307
PMCID:
PMC4412161
DOI:
10.1016/j.neuron.2014.07.010
[Indexed for MEDLINE]
Free PMC Article

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