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MBC in Press, published online ahead of print November 28, 2007
Mol. Biol. Cell 10.1091/mbc.E07-06-0625

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Submitted on July 2, 2007
Revised on November 6, 2007
Accepted on November 20, 2007

Transmembrane Domain Interactions Control Biological Functions Neuropilin-1

Lise Roth,* Cécile Nasarre,*{dagger} Sylvie Dirrig-Grosch,* Dominique Aunis,* Gérard Crémel,* Pierre Hubert,{ddagger} and Dominique Bagnard*

*INSERM U575 Physiopathologie du Système Nerveux, Université Louis Pasteur, Strasbourg, France; {dagger}PHARMAXON, IBDM, Marseille, France; {ddagger}LISM, Centre National de la Recherche Scientifique UPR 9027, Marseille, France

Monitoring Editor: Carl-Henrik Heldin

Neuropilin-1 (NRP1) is a transmembrane receptor playing a pivotal role in the control of semaphorins and VEGF signaling pathways. The exact mechanism controlling semaphorin receptor complex formation is unknown. A structural analysis and modeling of NRP1 revealed a putative dimerization GxxxG motif potentially important for NRP1 dimerization and oligomerization. Our data show that this motif mediates the dimerization of the transmembrane domain of NRP1 as demonstrated by a dimerization assay (ToxLuc assay) performed in natural membrane and FRET analysis. A synthetic peptide derived from the transmembrane segment of NRP1 abolished the inhibitory effect of Sema3A. This effect depends on the capacity of the peptide to interfere with NRP1 dimerization and the formation of oligomeric complexes. Mutation of the GxxxG dimerization motif in the transmembrane domain of NRP1 confirmed its biological importance for Sema3A signaling. Overall, our results shed light on an essential step required for semaphorin signaling and provide novel evidence for the crucial role of transmembrane domain of bitopic protein containing GxxxG motif in the formation of receptor complexes that are a prerequisite for cell signaling.

Address correspondence to: Dominique Bagnard (Dominique.Bagnard{at}inserm.u-strasbg.fr)






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