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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.

SUBMITTER: Xu K 

PROVIDER: S-EPMC4369087 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Xu Kai K   Wu Zhuhao Z   Renier Nicolas N   Antipenko Alexander A   Tzvetkova-Robev Dorothea D   Xu Yan Y   Minchenko Maria M   Nardi-Dei Vincenzo V   Rajashankar Kanagalaghatta R KR   Himanen Juha J   Tessier-Lavigne Marc M   Nikolov Dimitar B DB  

Science (New York, N.Y.) 20140529 6189


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  ...[more]

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