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TitleThe crystal structure of netrin-1 in complex with DCC reveals the bifunctionality of netrin-1 as a guidance cue.
Journal, issue, pagesNeuron, Vol. 83, Issue 4, Page 839-849, Year 2014
Publish dateAug 20, 2014
AuthorsLorenzo I Finci / Nina Krüger / Xiaqin Sun / Jie Zhang / Magda Chegkazi / Yu Wu / Gundolf Schenk / Haydyn D T Mertens / Dmitri I Svergun / Yan Zhang / Jia-Huai Wang / Rob Meijers /
PubMed AbstractNetrin-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 ...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.
External linksNeuron / PubMed:25123307 / PubMed Central
MethodsSAS (X-ray synchrotron) / X-ray diffraction
Resolution3.1 Å
Structure data

SASDA26:
DCC56 (Deleted in Colorectal Cancer (FN5 & FN6), dcc56)
Method: SAXS/SANS

SASDA76: NetrinVIV DCC56 complex (Netrin-1, NetrinVIV + Deleted in Colorectal Cancer (FN5 & FN6), dcc56)
Method: SAXS/SANS

SASDA86: NetrinVIV DCC56(M933R) complex (Netrin-1, NetrinVIV + Deleted in Colorectal Cancer (FN5 & FN6) M933R mutant, DCC56 (M933R))
Method: SAXS/SANS

SASDAZ5:
NetrinVIV (Netrin-1)
Method: SAXS/SANS

PDB-4urt:
The crystal structure of a fragment of netrin-1 in complex with FN5- FN6 of DCC
Method: X-RAY DIFFRACTION / Resolution: 3.1 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-CL:
Unknown entry

ChemComp-SO4:
SULFATE ION

ChemComp-GOL:
GLYCEROL

Source
  • homo sapiens (human)
KeywordsPROTEIN BINDING / APOPTOSIS / AXON GUIDANCE / DEPENDENCE RECEPTOR

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