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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Axons / physiology*
  • Cell Movement
  • DCC Receptor
  • Fibronectins / chemistry
  • Ligands
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / ultrastructure
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nerve Growth Factors / chemistry*
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / ultrastructure
  • Netrin Receptors
  • Netrin-1
  • Neurons / physiology
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / ultrastructure
  • Tumor Suppressor Proteins / chemistry*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / ultrastructure

Substances

  • DCC Receptor
  • Dcc protein, mouse
  • Fibronectins
  • Ligands
  • Membrane Proteins
  • Nerve Growth Factors
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • neogenin
  • Netrin-1

Associated data

  • PDB/4PLM
  • PDB/4PLN
  • PDB/4PLO