Lipid dynamics and lipid-protein interactions in rat hepatocyte plasma membranes.

ABSTRACTCell membranes contain hundreds of different proteins and lipids in an asymmetric arrangement. Understanding the lateral organization principles of these complex mixtures is essential for life and health. However, our current understanding of the detailed organization of cell membranes remains rather elusive, owing to the lack of experimental methods suitable for studying these fluctuating nanoscale assemblies of lipids and proteins with the required spatiotemporal resolution. Here, we use molecular dynamics simulations to characterize the lipid environment of ten membrane proteins. To provide a realistic lipid environment, the proteins are embedded in a model plasma membrane, where more than 60 lipid species are represented, asymmetrically distributed between leaflets. The simulations detail how each protein modulates its local lipid environment through local lipid composition, thickness, curvature and lipid dynamics. Our results provide a molecular glimpse of the complexity of lipid-protein interactions, with potentially far reaching implications for the overall organization of the cell membrane.

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Haemolytic actinoporins interact with carbohydrates using their lipid-binding module

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0216 ◽

2017 ◽

Vol 372 (1726) ◽

pp. 20160216 ◽

Cited By ~ 5

Author(s):

Koji Tanaka ◽

Jose M. M. Caaveiro ◽

Koldo Morante ◽

Kouhei Tsumoto

Keyword(s):

Protein Interactions ◽

Pore Formation ◽

Plasma Membranes ◽

Lipid Binding ◽

Target Cells ◽

Sea Anemones ◽

Molecular Systems ◽

Membrane Pores ◽

Living Organisms ◽

Lipid Protein Interactions

Pore-forming toxins (PFTs) are proteins endowed with metamorphic properties that enable them to stably fold in water solutions as well as in cellular membranes. PFTs produce lytic pores on the plasma membranes of target cells conducive to lesions, playing key roles in the defensive and offensive molecular systems of living organisms. Actinoporins are a family of potent haemolytic toxins produced by sea anemones vigorously studied as a paradigm of α-helical PFTs, in the context of lipid–protein interactions, and in connection with nanopore technologies. We have recently reported that fragaceatoxin C (FraC), an actinoporin, engages biological membranes with a large adhesive motif allowing the simultaneous attachment of up to four lipid molecules prior to pore formation. Since actinoporins also interact with carbohydrates, we sought to understand the molecular and energetic basis of glycan recognition by FraC. By employing structural and biophysical methodologies, we show that FraC engages glycans with low affinity using its lipid-binding module. Contrary to other PFTs requiring separate domains for glycan and lipid recognition, the small single-domain actinoporins economize resources by achieving dual recognition with a single binding module. This mechanism could enhance the recruitment of actinoporins to the surface of target tissues in their marine environment. This article is part of the themed issue ‘Membrane pores: from structure and assembly, to medicine and technology’.

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Lipid-mediated Association of the Slg1 Transmembrane Domains in Yeast Plasma Membranes

10.1101/2021.06.29.450341 ◽

2021 ◽

Author(s):

Azadeh Alavizargar ◽

Annegret Eltig ◽

Roland Wedlich Soeldner ◽

Andreas Heuer

Keyword(s):

Plasma Membrane ◽

Protein Interactions ◽

Plasma Membranes ◽

Acyl Chain ◽

Md Simulations ◽

Receptor Activation ◽

Transmembrane Domains ◽

Coarse Grained ◽

Self Association ◽

Lipid Protein Interactions

Clustering of transmembrane proteins underlies a multitude of fundamental biological processes at the plasma membrane such as receptor activation, lateral domain formation and mechanotransduction. The self-association of the respective transmembrane domains (TMD) has also been suggested to be responsible for the micron-scaled patterns seen for integral membrane proteins in the budding yeast plasma membrane (PM). However, the underlying interplay between local lipid composition and TMD identity is still not mechanistically understood. In this work we have used coarse-grained molecular dynamics (MD) simulations as well as microscopy experiments (TIRFM) to analyze the behavior of a representative helical yeast TMD (Slg1) within different lipid environments. Via the simulations we evaluated the effect of acyl chain saturation and the presence of anionic lipids head groups on the association of TMDs via simulations. Our simulations revealed that weak lipid-protein interactions significantly affect the configuration of TMD dimers and the free energy of association. Increased amounts of unsaturated phospholipids strongly reduced helix-helix interaction and the presence of phosphatidylserine (PS) lipids only slightly affected the dimer. Experimentally, the network factor, characterizing the association strength on a mesoscopic level, was measured in the presence and absence of PS lipids. Consistently with the simulations, no significant effect was observed. We also found that formation of TMD dimers in turn increased the order parameter of the surrounding lipids and induced long-range perturbations in lipid organization, shedding new light on the lipid-mediated dimerization of TMDs in complex lipid mixtures.

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Influence of phosphatidylserine on (Na+ + K+)-stimulated ATPase and acetylcholinesterase activities of dog brain synaptosomal plasma membranes

Biochemical Journal ◽

10.1042/bj2200301 ◽

1984 ◽

Vol 220 (1) ◽

pp. 301-307 ◽

Cited By ~ 107

Author(s):

S Tsakiris ◽

G Deliconstantinos

Keyword(s):

Protein Interactions ◽

Plasma Membranes ◽

Physiological Processes ◽

Maximal Stimulation ◽

Dog Brain ◽

The Central Nervous System ◽

Hill Coefficients ◽

Lipid Protein Interactions ◽

Synaptosomal Plasma Membranes ◽

Allosteric Properties

Phosphatidylserine (PtdSer) incubated with synaptosomal plasma membranes (SPM) of dog brain is incorporated into SPM in proportion to its concentration in the incubation medium. Low PtdSer concentrations progressively activated the SPM-associated (Na+ + K+)-stimulated ATPase and acetylcholinesterase. Increasing the PtdSer concentration above that which maximally stimulated the enzyme activities effected a progressive inhibition with respect to maximal stimulation. Arrhenius plots of (Na+ + K+ + Mg2+)-dependent ATPase and 5′-nucleotidase revealed a clear break at 23-24 degrees C for both enzymes in SPM untreated with PtdSer (controls), whereas a linear relation was obtained for SPM treated with PtdSer. Changes in the allosteric properties of (Na+ + K+)-stimulated ATPase by fluoride (F-) and/or of 5′-nucleotidase by concanavalin A (i.e. changes of Hill coefficients) indicate that PtdSer increases the membrane fluidity. These results suggest that modifications of lipid-protein interactions in SPM induced by PtdSer may have implications in the physiological processes in the central nervous system.

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Lipid–protein interactions in plasma membranes of fiber cells isolated from the human eye lens

Experimental Eye Research ◽

10.1016/j.exer.2014.01.018 ◽

2014 ◽

Vol 120 ◽

pp. 138-151 ◽

Cited By ~ 12

Author(s):

Marija Raguz ◽

Laxman Mainali ◽

William J. O'Brien ◽

Witold K. Subczynski

Keyword(s):

Protein Interactions ◽

Plasma Membranes ◽

Eye Lens ◽

Fiber Cells ◽

Human Eye ◽

Lipid Protein Interactions

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Model Membrane Systems Used to Study Plasma Membrane Lipid Asymmetry

Symmetry ◽

10.3390/sym13081356 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1356

Author(s):

Haden L. Scott ◽

Kristen B. Kennison ◽

Thais A. Enoki ◽

Milka Doktorova ◽

Jacob J. Kinnun ◽

...

Keyword(s):

Protein Interactions ◽

Plasma Membranes ◽

Membrane Lipid ◽

Model Membrane ◽

Model Membranes ◽

Computational Techniques ◽

Symmetric Model ◽

Membrane Asymmetry ◽

Asymmetric Model ◽

Lipid Protein Interactions

It is well known that the lipid distribution in the bilayer leaflets of mammalian plasma membranes (PMs) is not symmetric. Despite this, model membrane studies have largely relied on chemically symmetric model membranes for the study of lipid–lipid and lipid–protein interactions. This is primarily due to the difficulty in preparing stable, asymmetric model membranes that are amenable to biophysical studies. However, in the last 20 years, efforts have been made in producing more biologically faithful model membranes. Here, we review several recently developed experimental and computational techniques for the robust generation of asymmetric model membranes and highlight a new and particularly promising technique to study membrane asymmetry.

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CG2AT2: An Enhanced Fragment-based approach for Serial Multi-scale Molecular Dynamics simulations

10.1101/2021.03.25.437005 ◽

2021 ◽

Cited By ~ 1

Author(s):

Owen N. Vickery ◽

Phillip J. Stansfeld

Keyword(s):

Molecular Dynamics ◽

Protein Interactions ◽

Integral Membrane Protein ◽

Phospholipid Bilayer ◽

Coarse Grained ◽

Macromolecular Complex ◽

Macromolecular Complexes ◽

Lipid Dynamics ◽

Lipid Protein Interactions ◽

Dynamics Simulations

AbstractCoarse-grained molecular dynamics provides a means for simulating the assembly and interactions of macromolecular complexes at a reduced level of representation, thereby allowing both longer timescale and larger sized simulations. Here, we describe an enhanced fragment-based protocol for converting macromolecular complexes from coarse-grained to atomistic resolution, for further refinement and analysis. While the focus is upon systems that comprise an integral membrane protein embedded in a phospholipid bilayer, the technique is also suitable for e.g. membrane-anchored and soluble protein/nucleotide complexes. Overall, this provides a method for generating an accurate and well equilibrated atomic-level description of a macromolecular complex. The approach is evaluated using a diverse test set of eleven system configurations of vary size and complexity. Simulations are assessed in terms of protein stereochemistry, conformational drift, lipid/protein interactions, and lipid dynamics.

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