Lipid Rafts As a Membrane-Organizing Principle

Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Science (Impact Factor: 33.61). 01/2010; 327(5961):46-50. DOI: 10.1126/science.1174621
Source: PubMed


Cell membranes display a tremendous complexity of lipids and proteins designed to perform the functions cells require. To
coordinate these functions, the membrane is able to laterally segregate its constituents. This capability is based on dynamic
liquid-liquid immiscibility and underlies the raft concept of membrane subcompartmentalization. Lipid rafts are fluctuating
nanoscale assemblies of sphingolipid, cholesterol, and proteins that can be stabilized to coalesce, forming platforms that
function in membrane signaling and trafficking. Here we review the evidence for how this principle combines the potential
for sphingolipid-cholesterol self-assembly with protein specificity to selectively focus membrane bioactivity.

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    • "The spatial organization of many cell surface molecules is scale dependent, dynamic and is influenced by interaction with the actin cortex (Mayor & Rao, 2004; Hancock, 2006; Goswami et al, 2008; Lingwood & Simons, 2010; Gowrishankar et al, 2012), the thin layer of actin cytoskeleton that is juxtaposed to the bilayer. Although the cortical actin cytoskeleton is as yet poorly defined, there is growing evidence that it is composed simultaneously of dynamic filaments (Gowrishankar et al., 2012) and an extensively branched meshwork (Morone et al., 2006). "
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    ABSTRACT: Molecular diffusion at the surface of living cells is thought to be predominantly driven by thermal kicks. However, there is growing evidence that certain cell surface molecules are driven by the fluctuating dynamics of cortical cytoskeleton. Using fluorescence correlation spectroscopy (FCS) we measure the diffusion coefficient of a variety of cell-surface molecules over a temperature range 24-37°C. Predictably, exogenously incorporated fluorescent lipids with short acyl chains exhibit the expected increase of diffusion coefficient over this temperature range. In contrast, we find that GPI-anchored proteins exhibit temperature independent diffusion over this range, and revert to temperature-dependent diffusion on cell membrane blebs, in cells depleted of cholesterol, and upon acute perturbation of actin dynamics and myosin activity. A model transmembrane protein with a cytosolic actin-binding domain also exhibits the temperature independent behavior, thereby directly implicating the role of cortical actin. We show that diffusion of GPI-anchored proteins also becomes temperature-dependent when the filamentous dynamic actin nucleator, formin, is inhibited. However, changes in cortical actin mesh size or perturbation of branched actin nucleator Arp2/3 do not affect this behavior. Thus, the cell surface diffusion of GPI-anchored proteins and transmembrane protein that associate with actin, are driven by the active fluctuations of dynamic cortical actin filaments in addition to thermal fluctuations, consistent with expectations from an "active actin-membrane composite" cell surface.
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    • "Altogether, this shows that the floating fraction 5 contained high amounts of a lipid bilayer preferring lipids enrichment of cholesterol and caveolin and a low total amount of membrane proteins. It also demonstrates that DRM has a non-physiological appearance when compared to the L o lipid phase membrane microdomains in the living cell (Lingwood and Simons 2010). "
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    ABSTRACT: Lipid rafts are micro-domains of ordered lipids (L o phase) in biological membranes. The L o phase of cellular membranes can be isolated from disordered lipids (L d phase) after treatment with 1 % Triton X-100 at 4 °C in which the L o phase forms the detergent-resistant membrane (DRM) fraction. The lipid composition of DRM derived from Madin-Darby canine kidney (MDCK) cells, McArdle cells and por-cine sperm is compared with that of the whole cell. Remarkably, the unsaturation and chain length degree of aliphatic chains attached to phospholipids is virtually the same between DRM and whole cells. Cholesterol and sphingomyelin were enriched in DRMs but to a cell-specific molar ratio. Sulfatides (sphingolipids from MDCK cells) were enriched in the DRM while a seminolipid (an alkylacylglycerolipid from sperm) was depleted from the DRM. Treatment with<5 mM methyl-ß-cy-clodextrin (MBCD) caused cholesterol removal from the DRM without affecting the composition and amount of the phospholipid while higher levels disrupted the DRM. The substantial amount of (poly)unsaturated phospholipids in DRMs as well as a low stoichiometric amount of cholesterol suggest that lipid rafts in biological membranes are more fluid and dynamic than previously anticipated. Using negative staining, ultrastructural features of DRM were monitored and in all three cell types the DRMs appeared as multi-lamellar vesicular structures with a similar morphology. The detergent resistance is a result of protein–cholesterol and sphingolipid interactions allowing a relatively passive attraction of phospholipids to maintain the L o phase. For this special issue, the relevance of our findings is discussed in a sperm physiological context.
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    ABSTRACT: G proteins are fundamental elements in signal transduction involved in key cell responses, and their interactions with cell membrane lipids are critical events whose nature is not fully understood. Here, we have studied how the presence of myristic and palmitic acid moieties affects the interaction of the Gαi1 protein with model and biological membranes. For this purpose, we quantified the binding of purified Gαi1 protein and Gαi1 protein acylation mutants to model membranes, with lipid compositions that resemble different membrane microdomains. We observed that myristic and palmitic acids not only act as membrane anchors but also regulate Gαi1 subunit interaction with lipids characteristics of certain membrane microdomains. Thus, when the Gαi1 subunit contains both fatty acids it prefers raft-like lamellar membranes, with a high sphingomyelin and cholesterol content and little phosphatidylserine and phosphatidylethanolamine. By contrast, the myristoylated and non-palmitoylated Gαi1 subunit prefers other types of ordered lipid microdomains with higher phosphatidylserine content. These results in part explain the mobility of Gαi1 protein upon reversible palmitoylation to meet one or another type of signaling protein partner. These results also serve as an example of how membrane lipid alterations can change membrane signaling or how membrane lipid therapy can regulate the cell's physiology. Copyright © 2015. Published by Elsevier B.V.
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