title: The crystal structure of netrin-1 in complex with DCC reveals the bifunctionality of netrin-1 as a guidance cue.
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.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. 02215, USA.
authors.forename: Lorenzo I
authors.initials: LI
authors.lastname: Finci
authors.affiliation: European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Krüger
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Xiaqin
authors.initials: X
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Magda
authors.initials: M
authors.lastname: Chegkazi
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Gundolf
authors.initials: G
authors.lastname: Schenk
authors.affiliation: European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Haydyn D T
authors.initials: HDT
authors.lastname: Mertens
authors.affiliation: European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China.|PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. 02215, USA.
authors.forename: Jia-Huai
authors.initials: JH
authors.lastname: Wang
authors.affiliation: European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, 22607, Hamburg, Germany.
authors.forename: Rob
authors.initials: R
authors.lastname: Meijers
mesh_terms: D001369:Axons / Q000502:physiology*; D001665:Binding Sites; D002478:Cells, Cultured; D002633:Chemotaxis; D018360:Crystallography, X-Ray; D003463:Cues; D000075389:DCC Receptor; D019143:Evolution, Molecular; D008958:Models, Molecular; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000075389:DCC Receptor; C501909:DCC protein, human; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1