The Crystal Structure of Netrin-1 in Complex with DCC Reveals the Bifunctionality of Netrin-1 As a Guidance Cue

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2014 Aug 16

PMID 25123307

Citations 64

Authors

Lorenzo I Finci

Nina Kruger

Xiaqin Sun

Jie Zhang

Magda Chegkazi

Yu Wu

Gundolf Schenk

Haydyn D T Mertens

Dmitri I Svergun

Yan Zhang

Jia-Huai Wang

Rob Meijers

Affiliations

Soon will be listed here.

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.

Citing Articles

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TRIM9 Controls Growth Cone Responses to Netrin Through DCC and UNC5C.

Mutalik S, Ho C, OShaughnessy E, Frasineanu A, Shah A, Gupton S J Neurochem. 2025; 169(1):e70002.

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Mossy Fiber Sprouting in Temporal Lobe Epilepsy: The Impact of Netrin-1, DCC, and Gene Expression Changes.

Onay M, Harter P, Weber K, Piiper A, Czabanka M, Plate K Biomedicines. 2025; 12(12.

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