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Science. 2014 Jun 13;344(6189):1275-9. doi: 10.1126/science.1255149. Epub 2014 May 29.

Neural migration. Structures of netrin-1 bound to two receptors provide insight into its axon guidance mechanism.

Author information

1
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA.
3
Department of Chemistry and Chemical Biology, Cornell University and Northeastern Collaborative Access Team, Advanced Photon Source, Argonne, IL 60439, USA.
4
Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA. nikolovd@mskcc.org marctl@mail.rockefeller.edu.
5
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. nikolovd@mskcc.org marctl@mail.rockefeller.edu.

Abstract

Netrins are secreted proteins that regulate axon guidance and neuronal migration. Deleted in colorectal cancer (DCC) is a well-established netrin-1 receptor mediating attractive responses. We provide evidence that its close relative neogenin is also a functional netrin-1 receptor that acts with DCC to mediate guidance in vivo. We determined the structures of a functional netrin-1 region, alone and in complexes with neogenin or DCC. Netrin-1 has a rigid elongated structure containing two receptor-binding sites at opposite ends through which it brings together receptor molecules. The ligand/receptor complexes reveal two distinct architectures: a 2:2 heterotetramer and a continuous ligand/receptor assembly. The differences result from different lengths of the linker connecting receptor domains fibronectin type III domain 4 (FN4) and FN5, which differs among DCC and neogenin splice variants, providing a basis for diverse signaling outcomes.

PMID:
24876346
PMCID:
PMC4369087
DOI:
10.1126/science.1255149
[Indexed for MEDLINE]
Free PMC Article
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