Neural migration. Structures of netrin-1 bound to two receptors provide insight into its axon guidance mechanism.
Publication Type:Journal Article
Source:Science, Volume 344, Issue 6189, p.1275-9 (2014)
Keywords:Animals, Axons, Cell Movement, Fibronectins, Ligands, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Nerve Growth Factors, Neurons, Protein Multimerization, Protein Structure, Tertiary, Receptors, Cell Surface, Tumor Suppressor Proteins
<p>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.</p>