Lipid raft

The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence remains very controversial. It has been proposed that they are specialised membrane microdomains which compartmentalise cellular processes by serving as organising centers for the assembly of signaling molecules, allowing a closer interaction of protein receptors and their effectors to promote kinetically favorable interactions necessary for the signal transduction. Lipid rafts influences membrane fluidity and membrane protein trafficking, then regulating neurotransmission and receptor trafficking. Lipid rafts are more ordered and tightly packed than the surrounding bilayer, but float freely in the membrane bilayer. Although more common in the cell membrane, lipid rafts have also been reported in other parts of the cell, such as the Golgi apparatus and lysosomes. The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence remains very controversial. It has been proposed that they are specialised membrane microdomains which compartmentalise cellular processes by serving as organising centers for the assembly of signaling molecules, allowing a closer interaction of protein receptors and their effectors to promote kinetically favorable interactions necessary for the signal transduction. Lipid rafts influences membrane fluidity and membrane protein trafficking, then regulating neurotransmission and receptor trafficking. Lipid rafts are more ordered and tightly packed than the surrounding bilayer, but float freely in the membrane bilayer. Although more common in the cell membrane, lipid rafts have also been reported in other parts of the cell, such as the Golgi apparatus and lysosomes. One key difference between lipid rafts and the plasma membranes from which they are derived is lipid composition. Research has shown that lipid rafts contain 3 to 5-fold the amount of cholesterol found in the surrounding bilayer. Also, lipid rafts are enriched in sphingolipids such as sphingomyelin, which is typically elevated by 50% compared to the plasma membrane. To offset the elevated sphingolipid levels, phosphatidylcholine levels are decreased which results in similar choline-containing lipid levels between the rafts and the surrounding plasma membrane. Cholesterol interacts preferentially, although not exclusively, with sphingolipids due to their structure and the saturation of the hydrocarbon chains. Although not all of the phospholipids within the raft are fully saturated, the hydrophobic chains of the lipids contained in the rafts are more saturated and tightly packed than the surrounding bilayer. Cholesterol is the dynamic 'glue' that holds the raft together. Due to the rigid nature of the sterol group, cholesterol partitions preferentially into the lipid rafts where acyl chains of the lipids tend to be more rigid and in a less fluid state. One important property of membrane lipids is their amphipathic character. Amphipathic lipids have a polar, hydrophilic head group and a non-polar, hydrophobic region. The figure to the right shows the inverted cone-like shape of sphingomyelin and the cone-like shape of cholesterol based on the area of space occupied by the hydrophobic and hydrophilic regions. Cholesterol can pack in between the lipids in rafts, serving as a molecular spacer and filling any voids between associated sphingolipids. Rietveld & Simons related lipid rafts in model membranes to the immiscibility of ordered (Lo phase) and disordered (Ld or Lα phase) liquid phases. The cause of this immiscibility is uncertain, but the immiscibility is thought to minimize the free energy between the two phases. Studies have shown there is a difference in thickness of the lipid rafts and the surrounding membrane which results in hydrophobic mismatch at the boundary between the two phases. This phase height mismatch has been shown to increase line tension which may lead to the formation of larger and more circular raft platforms to minimize the energetic cost of maintaining the rafts as a separate phase. Other spontaneous events, such as curvature of the membrane and fusing of small rafts into larger rafts, can also minimize line tension. By one early definition of lipid rafts, lipid rafts differ from the rest of the plasma membrane. In fact, researchers have hypothesized that the lipid rafts can be extracted from a plasma membrane. The extraction would take advantage of lipid raft resistance to non-ionic detergents, such as Triton X-100 or Brij-98 at low temperatures (e.g., 4 °C). When such a detergent is added to cells, the fluid membrane will dissolve while the lipid rafts may remain intact and could be extracted. Because of their composition and detergent resistance, lipid rafts are also called detergent-insoluble glycolipid-enriched complexes (GEMs) or DIGs or Detergent Resistant Membranes (DRMs). However the validity of the detergent resistance methodology of membranes has recently been called into question due to ambiguities in the lipids and proteins recovered and the observation that they can also cause solid areas to form where there were none previously. Until 1982, it was widely accepted that phospholipids and membrane proteins were randomly distributed in cell membranes, according to the Singer-Nicolson fluid mosaic model, published in 1972. However, membrane microdomains were postulated in the 1970s using biophysical approaches by Stier & Sackmann and Klausner & Karnovsky. These microdomains were attributed to the physical properties and organization of lipid mixtures by Stier & Sackmann and Israelachvili et al. In 1974, the effects of temperature on membrane behavior had led to the proposal of 'clusters of lipids' in membranes and by 1975, data suggested that these clusters could be 'quasicrystalline' regions within the more freely dispersed liquid crystalline lipid molecule. In 1978, X-Ray diffraction studies led to further development of the 'cluster' idea defining the microdomains as 'lipids in a more ordered state'. Karnovsky and co-workers formalized the concept of lipid domains in membranes in 1982. Karnovsky's studies showed heterogeneity in the lifetime decay of 1,6-diphenyl-1,3,5-hexatriene, which indicated that there were multiple phases in the lipid environment of the membrane. One type of microdomain is constituted by cholesterol and sphingolipids. They form because of the segregation of these lipids into a separate phase, demonstrated by Biltonen and Thompson and their coworkers. These microdomains (‘rafts’) were shown to exist also in cell membranes. Later, Kai Simons at the European Molecular Biology Laboratory (EMBL) in Germany and Gerrit van Meer from the University of Utrecht, Netherlands refocused interest on these membrane microdomains, enriched with lipids and cholesterol, glycolipids, and sphingolipids, present in cell membranes. Subsequently, they called these microdomains, lipid 'rafts'. The original concept of rafts was used as an explanation for the transport of cholesterol from the trans Golgi network to the plasma membrane. The idea was more formally developed in 1997 by Simons and Ikonen. At the 2006 Keystone Symposium of Lipid Rafts and Cell Function, lipid rafts were defined as 'small (10-200nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein-protein interactions' In recent years, lipid raft studies have tried to address many of the key issues that cause controversy in this field, including the size and lifetime of rafts.