title: Neural migration. Structures of netrin-1 bound to two receptors provide insight into its axon guidance mechanism.
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.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Xu
authors.affiliation: Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA.
authors.forename: Zhuhao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renier
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Antipenko
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Tzvetkova-Robev
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Minchenko
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nardi-Dei
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University and Northeastern Collaborative Access Team, Advanced Photon Source, Argonne, IL 60439, USA.
authors.forename: Kanagalaghatta R
authors.initials: KR
authors.lastname: Rajashankar
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Juha
authors.initials: J
authors.lastname: Himanen
authors.affiliation: Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA. nikolovd@mskcc.org marctl@mail.rockefeller.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. nikolovd@mskcc.org marctl@mail.rockefeller.edu.
authors.forename: Dimitar B
authors.initials: DB
authors.lastname: Nikolov
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002465:Cell Movement; D000075389:DCC Receptor; D005353:Fibronectins / Q000737:chemistry; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000502:physiology; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure
chemical_list: D000075389:DCC Receptor; C501910:Dcc protein, mouse; D005353:Fibronectins; D008024:Ligands; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C091279:neogenin; D000075388:Netrin-1