Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex
Co-receptors add complexity to cell-cell signaling systems. The secreted semaphorin 3s (Sema3s) require a co-receptor, neuropilin (Nrp), to signal through plexin As (PlxnAs) in functions ranging from axon guidance to bone homeostasis, but the role of the co-receptor is obscure. Here we present the l...
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Published in | Nature structural & molecular biology Vol. 19; no. 12; pp. 1293 - 1299 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Nature Publishing Group
01.12.2012
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Subjects | |
Online Access | Get full text |
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Summary: | Co-receptors add complexity to cell-cell signaling systems. The secreted semaphorin 3s (Sema3s) require a co-receptor, neuropilin (Nrp), to signal through plexin As (PlxnAs) in functions ranging from axon guidance to bone homeostasis, but the role of the co-receptor is obscure. Here we present the low-resolution crystal structure of a mouse semaphorin-plexin-Nrp complex alongside unliganded component structures. Dimeric semaphorin, two copies of plexin and two copies of Nrp are arranged as a dimer of heterotrimers. In each heterotrimer subcomplex, semaphorin contacts plexin, similar to in co-receptor-independent signaling complexes. The Nrp1s cross brace the assembly, bridging between sema domains of the Sema3A and PlxnA2 subunits from the two heterotrimers. Biophysical and cellular analyses confirm that this Nrp binding mode stabilizes a canonical, but weakened, Sema3-PlxnA interaction, adding co-receptor control over the mechanism by which receptor dimerization and/or oligomerization triggers signaling. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work Present address: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands B.J.C.J., T.M., C.S. and E.Y.J. designed the project. B.J.C.J. and E.Y.J. wrote the manuscript with input from all authors. B.J.C.J. produced the constructs for crystallization, performed MALS, crystallization, diffraction data collection, structure solution and refinement. T.M. and B.J.C.J. cloned and produced constructs for SPR experiments and performed SPR experiments. T.M. did the Western blot analysis. T.M. produced proteins for growth cone collapse assays which G.A.W. performed under supervision of M.Z.C. Author Contributions |
ISSN: | 1545-9993 1545-9985 |
DOI: | 10.1038/nsmb.2416 |