TY - JOUR

T1 - Mechanism of Shiga Toxin Clustering on Membranes

AU - Pezeshkian, Weria

AU - Gao, Haifei

AU - Arumugam, Senthil

AU - Becken, Ulrike

AU - Bassereau, Patricia

AU - Florent, Jean-Claude

AU - Ipsen, John Hjort

AU - Johannes, Ludger

AU - Shillcock, Julian C.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Casimir force

KW - fluctuation-induced force

KW - endocytosis

KW - invagination

KW - membrane

KW - clustering glycosphingolipid

KW - lectin

KW - FLUCTUATION-INDUCED INTERACTIONS

KW - MEDIATED INTERACTIONS

KW - LIPID INTERACTIONS

KW - FLUID MEMBRANES

KW - INDUCED FORCES

KW - INCLUSIONS

KW - CURVATURE

KW - CELLS

KW - ATTRACTION

KW - INTERFACES

U2 - 10.1021/acsnano.6b05706

DO - 10.1021/acsnano.6b05706

M3 - Journal article

VL - 11

SP - 314

EP - 324

JO - A C S Nano

JF - A C S Nano

SN - 1936-0851

IS - 1

ER -