Lipid Raft Formation: Key Role of Polyunsaturated Phospholipids

Abstract

The forces that drive lipid raft formation are poorly understood. To date, most of the attention has focused on attractive interactions between cholesterol and high-melting lipids. Remarkably little attention has been paid to repulsive forces. Here, we show that repulsive interactions between an exchangeable mimic of cholesterol and an exchangeable mimic of a low-melting phospholipid in liquid-disordered bilayers can be much stronger than the attractive forces between this same sterol and an exchangeable mimic of a high-melting phospholipid in liquid-ordered bilayers. We conclude that polyunsaturated phospholipids have been largely overlooked as major players in lipid raft formation. This knowledge should stimulate considerable interest in controlling the levels of polyunsaturated phospholipids for the proper functioning of cell membranes.

Shiga toxin binding alters lipid packing and the domain structure of Gb3-containing membranes: a solid-state NMR study

“…26,29 As membrane lipids are ubiquitous, highly abundant, and relatively similar in their chemical structure, investigation of specific lipid-protein interactions by biophysical methods rests on an important prerequisite: specific lipid molecules are required that contain functional groups such as (i) fluorescence or EPR labels, [30][31][32] (ii) isotopic enrichment, 22,33 or (iii) functional groups for cross linking with other lipids or proteins. 34 Here, we have used specifically deuterated Gb 3 lipids in interaction studies with STxB by solid-state 2 H NMR spectroscopy. Isotopic enrichment is a very well established method allowing highlighting protein interaction with specific lipids.…”

Supramolecular Chemistry in the Biomembrane

“…The intermolecular reaction between 28 and 30 to release yellow‐colored pyridine‐2‐thiol is supposed to proceed very slowly, whereas disulfide formation at the outer leaflet by oxidation brings the disulfide and thiol on the inner leaflet into close proximity, leading to a pronounced increase in reaction rate. Notably, disulfide exchange, which is also very popular in dynamic combinatorial chemistry, has been extensively exploited by Regen and co‐workers in lipid membranes to map the lateral organization of lipid bilayers, to address the mysterious mechanism of action of general anesthetics, such as chloroform, and to shine light on the driving forces of lipid raft formation …”

“…Notably, disulfide exchange, which is also very popular in dynamic combinatorial chemistry, [61] has been extensively exploited by Regen and co-workers in lipid membranes to map the lateral organization of lipid bilayers, [62] to address the mysterious mechanism of action of general anesthetics, such as chloroform, [63] and to shine light on the driving forces of lipid raft formation. [64] To afford the desired asymmetric orientation of 30 in the lipid bilayer, compound 29 was used in the preparation of the vesicle and external disulfide was removed by the addition of tris (3-sulfonatophenyl)phosphane, which was a charged, and thus, membrane-impermeable reducing agent. This affords membrane-bound 30, in which all disulfide units are located on the inside of the vesicles.…”

Lipid Raft Formation Driven by Push and Pull Forces

“…To quantify the repulsive interactions between cholesterol and low-melting phospholipids in the liquid-disordered phase, we examined the mixing behavior of 4, 5 and 6 with 3 in host membranes that were in liquiddisordered bilayers at 45°C (Figure 7). 24 We have used the ciscyclopropyl groups to lock in permanent "kinks" in the acyl chains instead of cis-double bonds to avoid any possibility of cis/trans isomerization under NNR conditions. In previous work, we have found that such isomerization is possible, apparently due to the formation of small amounts of thiyl radical being produced.…”