Format

Send to

Choose Destination
PLoS One. 2014 May 23;9(5):e97779. doi: 10.1371/journal.pone.0097779. eCollection 2014.

Transmembrane recognition of the semaphorin co-receptors neuropilin 1 and plexin A1: coarse-grained simulations.

Author information

1
Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique UPR, Université d'Orléans, Orléans, France.
2
Laboratoire d'Ingénierie des Systèmes Macromoléculaires UMR, Université d'Aix-Marseille, Marseille, France.
3
Institut National de la Santé et de la Recherche Médicale, Labex Medalis, Université de Strasbourg, Strasbourg, France.

Abstract

The cancer associated class 3 semaphorins require direct binding to neuropilins and association to plexins to trigger cell signaling. Here, we address the role of the transmembrane domains of neuropilin 1 and plexin A1 for the dimerization of the two receptors by characterizing the assembly in lipid bilayers using coarse-grained molecular dynamics simulations. From experimental evidence using a two-hybrid system showing the biochemical association of the two receptors transmembrane domains, we performed molecular simulations in DOPC and POPC demonstrating spontaneously assembly to form homodimers and heterodimers with a very high propensity for right-handed packing of the helices. Inversely, left-handed packing was observed with a very low propensity. This mode of packing was observed uniquely when the plexin A1 transmembrane domain was involved in association. Potential of mean force calculations were used to predict a hierarchy of self-association for the monomers: the two neuropilin 1 transmembrane domains strongly associated, neuropilin 1 and plexin A1 transmembrane domains associated less and the two plexin A1 transmembrane domains weakly but significantly associated. We demonstrated that homodimerization and heterodimerization are driven by GxxxG motifs, and that the sequence context modulates the packing mode of the plexin A1 transmembrane domains. This work presents major advances towards our understanding of membrane signaling platforms assembly through membrane domains and provides exquisite information for the design of antagonist drugs defining a novel class of therapeutic agents.

PMID:
24858828
PMCID:
PMC4032258
DOI:
10.1371/journal.pone.0097779
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center