期刊
SCIENCE
卷 344, 期 6189, 页码 1275-1279出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1255149
关键词
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资金
- National Institute of General Medical Sciences from NIH [P41 GM103403]
- U.S. DOE [DE-AC02-06CH11357]
- Bristol-Myers Squibb postdoctoral fellowship at the Rockefeller University
- European Molecular Biology Organization long-term postdoctoral fellowship
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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