title: Mechanism of Shiga Toxin Clustering on Membranes.
abstract: The bacterial Shiga toxin interacts with its cellular receptor, the glycosphingolipid globotriaosylceramide (Gb3 or CD77), as a first step to entering target cells. Previous studies have shown that toxin molecules cluster on the plasma membrane, despite the apparent lack of direct interactions between them. The precise mechanism by which this clustering occurs remains poorly defined. Here, we used vesicle and cell systems and computer simulations to show that line tension due to curvature, height, or compositional mismatch, and lipid or solvent depletion cannot drive the clustering of Shiga toxin molecules. By contrast, in coarse-grained computer simulations, a correlation was found between clustering and toxin nanoparticle-driven suppression of membrane fluctuations, and experimentally we observed that clustering required the toxin molecules to be tightly bound to the membrane surface. The most likely interpretation of these findings is that a membrane fluctuation-induced force generates an effective attraction between toxin molecules. Such force would be of similar strength to the electrostatic force at separations around 1 nm, remain strong at distances up to the size of toxin molecules (several nanometers), and persist even beyond. This force is predicted to operate between manufactured nanoparticles providing they are sufficiently rigid and tightly bound to the plasma membrane, thereby suggesting a route for the targeting of nanoparticles to cells for biomedical applications.
authors.affiliation: Center for Biomembrane Physics (MEMPHYS), Department of Physics, Chemistry and Pharmacy (FKF), University of Southern Denmark , Campusvej 55, 5230 Odense M, Denmark.|TRANSPOL Molecular Neurobiochemistry, Ruhr Universität Bochum , 44801 Bochum, Germany.
authors.forename: Weria
authors.initials: W
authors.lastname: Pezeshkian
authors.affiliation: Institut Curie, PSL Research University , Chemical Biology of Membranes and Therapeutic Delivery unit, INSERM U 1143, CNRS UMR 3666, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.|TRANSPOL Molecular Neurobiochemistry, Ruhr Universität Bochum , 44801 Bochum, Germany.
authors.forename: Haifei
authors.initials: H
authors.lastname: Gao
authors.affiliation: Institut Curie, PSL Research University , Chemical Biology of Membranes and Therapeutic Delivery unit, INSERM U 1143, CNRS UMR 3666, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.|Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, CNRS UMR16855216 , 75248 Cedex 05 Paris, France.
authors.forename: Senthil
authors.initials: S
authors.lastname: Arumugam
authors.affiliation: Institut Curie, PSL Research University , Chemical Biology of Membranes and Therapeutic Delivery unit, INSERM U 1143, CNRS UMR 3666, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Becken
authors.affiliation: Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, CNRS UMR16855216 , 75248 Cedex 05 Paris, France.|Sorbonne Universités, UPMC Univ Paris 06 , 75005 Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bassereau
authors.affiliation: Institut Curie, PSL Research University , Chemical Biology of Membranes and Therapeutic Delivery unit, INSERM U 1143, CNRS UMR 3666, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Florent
authors.affiliation: Center for Biomembrane Physics (MEMPHYS), Department of Physics, Chemistry and Pharmacy (FKF), University of Southern Denmark , Campusvej 55, 5230 Odense M, Denmark.
authors.forename: John Hjort
authors.initials: JH
authors.lastname: Ipsen
authors.affiliation: Institut Curie, PSL Research University , Chemical Biology of Membranes and Therapeutic Delivery unit, INSERM U 1143, CNRS UMR 3666, 26 rue d'Ulm, 75248 Cedex 05 Paris, France.
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.affiliation: Ecole polytechnique fédérale de Lausanne (EPFL) , 1015 Lausanne, Switzerland.
authors.forename: Julian C
authors.identifier: 0000-0002-7885-735X
authors.initials: JC
authors.lastname: Shillcock
mesh_terms: D002462:Cell Membrane / Q000737:chemistry*; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry*; D022621:Shiga Toxin / Q000737:chemistry*; D055672:Static Electricity; D014281:Trihexosylceramides / Q000737:chemistry*
chemical_list: D014281:Trihexosylceramides; C018549:globotriaosylceramide; D022621:Shiga Toxin
keywords: Casimir force; clustering; endocytosis; fluctuation-induced force; glycosphingolipid; invagination; lectin; membrane