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

• Published in: PloS one Vol. 9; no. 5; p. e97779
• Main Authors: Aci-Sèche, Samia, Sawma, Paul, Hubert, Pierre, Sturgis, James N, Bagnard, Dominique, Jacob, Laurent, Genest, Monique, Garnier, Norbert
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23-05-2014; Public Library of Science (PLoS)
• Subjects: Assembly; Biology and Life Sciences; Cancer; Cell Membrane - metabolism; Chemical compounds; Dimerization; Drug development; Handedness; Helices; Humans; Hybrid systems; Kinases; Life Sciences; Ligands; Lipid bilayers; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Molecular dynamics; Molecular Dynamics Simulation; Monomers; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neuropilin; Neuropilin-1 - chemistry; Neuropilin-1 - metabolism; Packing; Pharmacology; Phosphatidylcholines - metabolism; Protein Multimerization; Protein Structure, Quaternary; Proteins; Receptors; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Self-association; Semaphorins; Semaphorins - metabolism; Signal transduction; Signaling; Simulation; Thermodynamics; Transmembrane domains; France; Transmembrane receptors; Lipids; Sequence motif analysis; Dimerization; Biochemical simulations; Free energy; Dimers (Chemical physics); Membrane receptor signaling
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0097779

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.