Nanodomain Formation of Ganglioside GM1 in Lipid Membrane: Effects of Cholera Toxin-Mediated Cross-Linking

Sun, Huijiao; Chen, Licui; Ling, Gao; Fang, Wei‐Hai

doi:10.1021/acs.langmuir.5b01866

Cited by 29 publications

(28 citation statements)

References 51 publications

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“…This study will enable one to utilize the current data for designing structural based drug inhibitors of this enzyme. Similarly, this work will further enhance the validity of the previously published experimental models [16,23] that utilized an array of biophysical and physiochemical methods and a variety of experimental conditions. This work will also be a stimulus for the beginning of MD simulation based docking, as the static structures of molecules are relatively less informative as compared to the dynamic structure of the protein -ligand system.…”

Section: Introductionmentioning

confidence: 74%

“…Currently more than 10 well resolved crystal structures of CT are available [2,11,21,22] and they off er a base for designing potent inhibitors against this toxin through a structure-based approach by using molecular modeling and dynamics simulation [22,23]. The mode of action of CT showed several important steps that can be exploited for drug design [22].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

2016

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A molecular dynamics (MD) simulation study of the enzymatic portion of cholera toxin; cholera toxin A-1 polypeptide (CTA1) was performed at 283, 310 and 323 K. From total energy analysis it was observed that this toxin is stable thermodynamically and these outcomes were likewise confirmed by root mean square deviations (RMSD) investigations. The Cα root mean square fluctuation (RMSF) examinations revealed that there are a number of residues inside CTA1, which can be used as target for designing and synthesizing inhibitory drugs, in order to inactivate cholera toxin inside the human body. The fluctuations in the radius of gyration and hydrogen bonding in CTA1 proved that protein unfolding and refolding were normal routine phenomena in its structure at all temperatures. Solvent accessible surface area study identified the hydrophilic nature of the CTA1, and due to this property it can be a potential biological weapon. The structural identification (STRIDE) algorithm for proteins was successfully used to determine the partially disordered secondary structure of CTA1. On account of this partially disordered secondary structure, it can easily deceive the proteolytic enzymes of the endoplasmic reticulum of host cells.

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

2016

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“…A link between GM1, pinning and interdigitation has recently been found in both simulations and model membrane studies (Spillane et al, 2014; Sun et al, 2015). It seems likely that the lo-domain formation observed in the plasma membrane after cross-linking outer leaflet components, described above, causes the pinned molecules to stretch and hence make contact with the inner leaflet lipids, both nucleating and stabilizing the domains.…”

Section: Pinningmentioning

confidence: 68%

“…In molecular dynamics (MD) simulations of asymmetric bilayers, lo-domains in one leaflet can induce registered ordered domains in an opposing leaflet with a composition that on its own would not allow lo-domain formation (Perlmutter and Sachs, 2011; Polley et al, 2014). MD simulations and theoretical considerations have also suggested the opposite possibility that membrane fluidisation in one leaflet may cause a decrease in the order of or even prevent phase separation in the opposing leaflet (Wagner et al, 2007; Sun et al, 2015). In asymmetric supported bilayers, lo-domains on the supported side can induce lo-domains in the free side with inner leaflet lipid mixes that only form ld-phase on their own (Kiessling et al, 2006), a process that was later shown to require acyl chain diversity among the inner leaflet lipids (Wan et al, 2008).…”

Section: Lipid Asymmetry In the Plasma Membranementioning

confidence: 99%

Interleaflet Coupling, Pinning, and Leaflet Asymmetry—Major Players in Plasma Membrane Nanodomain Formation

Fujimoto

Parmryd

2017

Front. Cell Dev. Biol.

116

114

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The plasma membrane has a highly asymmetric distribution of lipids and contains dynamic nanodomains many of which are liquid entities surrounded by a second, slightly different, liquid environment. Contributing to the dynamics is a continuous repartitioning of components between the two types of liquids and transient links between lipids and proteins, both to extracellular matrix and cytoplasmic components, that temporarily pin membrane constituents. This make plasma membrane nanodomains exceptionally challenging to study and much of what is known about membrane domains has been deduced from studies on model membranes at equilibrium. However, living cells are by definition not at equilibrium and lipids are distributed asymmetrically with inositol phospholipids, phosphatidylethanolamines and phosphatidylserines confined mostly to the inner leaflet and glyco- and sphingolipids to the outer leaflet. Moreover, each phospholipid group encompasses a wealth of species with different acyl chain combinations whose lateral distribution is heterogeneous. It is becoming increasingly clear that asymmetry and pinning play important roles in plasma membrane nanodomain formation and coupling between the two lipid monolayers. How asymmetry, pinning, and interdigitation contribute to the plasma membrane organization is only beginning to be unraveled and here we discuss their roles and interdependence.

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“…Thus, ceramide structure could impact the raft association of cross-linked GM1, which is credited with the membrane bending and internalization of CTxB in cells (31,(54)(55)(56). Variation in the ceramide tail structure may alter the composition and acyl-tail order of GM1-rich nanoscopic domains (37,57,58). Accordingly, the spontaneous recruitment of liquid-order preferring lipids and the line tension surrounding the GM1-rich domain are likely to depend on the ceramide structure.…”

Section: Discussionmentioning

confidence: 99%

Structured clustering of the glycosphingolipid GM1 is required for membrane curvature induced by cholera toxin

Kabbani

Raghunathan

Lencer

et al. 2020

Preprint

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AB5 bacterial toxins and polyomaviruses induce membrane curvature as a mechanism to facilitate their entry into host cells. How membrane bending is accomplished is not yet fully understood but has been linked to the simultaneous binding of the pentameric B-subunit to multiple copies of their glycosphingolipid receptors. Here, we probe the toxin membrane binding and internalization mechanisms by using a combination of super-resolution and polarized localization microscopy. We show that cholera toxin subunit B (CTxB) can induce membrane curvature only when bound to multiple copies of its glycosphingolipid receptor, GM1, and the ceramide structure of GM1 is likely not a determinant of this activity as assessed in model membranes. A mutant CTxB capable of binding only a single GM1 fails to generate curvature either in model membranes or in cells and clustering the mutant CTxB-single-GM1 complexes by antibody cross-linking does not rescue the membrane curvature phenotype. We conclude that both the multiplicity and specific geometry of GM1 binding sites are necessary for the induction of membrane curvature. We expect this to be a general rule of membrane behavior for all AB5 toxins and polyomaviruses that bind glycosphingolipids to invade host cells.SIGNIFICANCE STATEMENTMembrane binding toxins demonstrate both a public health challenge and a bioengineering opportunity due to their efficient internalization into cells. These toxins multivalently bind to naturally occurring lipid receptors at the plasma membrane and initiate endocytosis. This manuscript reports the importance of structured lipid-receptor clustering for the induction of membrane bending. We also observed that the magnitude of membrane curvature was correlated to the stoichiometry of toxin-bound receptors. By identifying how these bacterial proteins initiate membrane curvature, these findings provide mechanistic insights into the early steps of pathogenic endocytosis.

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Nanodomain Formation of Ganglioside GM1 in Lipid Membrane: Effects of Cholera Toxin-Mediated Cross-Linking

Cited by 29 publications

References 51 publications

Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

Interleaflet Coupling, Pinning, and Leaflet Asymmetry—Major Players in Plasma Membrane Nanodomain Formation

Structured clustering of the glycosphingolipid GM1 is required for membrane curvature induced by cholera toxin

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