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

Science  13 Jun 2014:
Vol. 344, Issue 6189, pp. 1275-1279
DOI: 10.1126/science.1255149

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Dissecting how signaling directs axon growth

During development of the nervous system, nerve cells send out projections called axons that must be guided to their proper targets. Netrins are secreted proteins that bind to receptors to either attract or repel the growing axons. Xu et al. present x-ray structures that show that complexes of netrin with two different receptors, neogenin and DCC, have different architectures. How netrin signals remains to be understood in detail, but netrin's ability to create different assemblies probably plays a role in the diverse signaling outcomes it mediates.

Science, this issue p. 1275

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.

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