Lipid raft

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A lipid raft is a cholesterol-enriched microdomain in cell membranes.

Since 1972, it has been believed that, in cell membranes, phospholipids and membrane proteins are ubiquitously distributed according to a fluid mosaic model (Singer & Nicholson, 1972). However, in 1988, Kai Simons at the European Molecular Biology Laboratory (EMBL) in Germany and Gerrit van Meer from the University of Utrecht, Netherlands suggested the novel idea that there exist microdomains, which are enriched with many kinds of lipids such as cholesterol, glycolipids, and sphingolipids, present in cell membranes (Simons & van Meer, 1988). This was the first time these microdomains were called "lipid rafts". The original concept of rafts was used as an explanation for the transport of cholesterol from the trans-Golgi to the plasma membrane. The idea was more formally developed in 1997 by Simons and Ikonen (Ikonen & Simons 1997).

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[edit] Properties of lipid rafts

The concept of lipid rafts has been related to the liquid-liquid immiscibility observed within model membranes reported between the liquid ordered phase (Lo phase) and the liquid disordered phase (Ld or Lα phase) (Rietveld & Simons, 1998). Although the exact cause remains uncertain, this immiscibility is thought to arise in order to minimize the free energy between the two phases.

One of the original definitions of lipid rafts is that they differed from the rest of the plasma membrane. They are resistant to non-ionic detergents, such as Triton X-100 or Brij-98 at low temperatures e.g. 4°C. When the detergent is added to cells, it has been hypothesised that the fluid membrane will dissolve while the lipid rafts will remain intact and can be extracted. Because of their composition and detergent resistance, lipid rafts may also be referred to as detergent-insoluble, glycolipid-enriched complexes (GEMs), or DIGs (Dietrich & Jacobson, 1999) or Detergent Resistant Membranes (DRMs). However the validity of the detergent resistance methodology of membranes has recently been called into question (Heerklotz, 2002) 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.

[edit] Examples

Certain proteins associated with cellular signaling processes have been shown to associate with lipid rafts (Brown & Rose, 1992). Proteins that have shown association to the lipid rafts include glycosylphosphatidylinositol(GPI)-anchored proteins, doubly-acylated tyrosine kinases of the Src family, and transmembrane proteins. This association can at least be partially contributed to the acylated, saturated tails of both the tyrosine kinases and the GPI-anchored proteins, which matches the properties of sphingolipids more so than the rest of the membrane (Simons & Ikonen, 1997). While these proteins tend to continuously be present in lipid rafts, there are others that associate with lipid rafts only when the protein is activated. Some examples of these include, but are not limited to, B cell receptors (BCRs), T cell receptors (TCRs), PAG, and an enzyme called CD39 (Horejsí et al, 1999; Matko & Szollosi, 2002; Papanikolaou et al, 2005; Petrie et al, 2000). Other proteins are excluded from rafts, such as transferrin-receptor and a member of the Ras familly. Typically the inclusion or exclusion of proteins is derermined by whether or not they are found in membrane fragments extracted using Triton - the DRM definition of a raft.

Researchers have tested the presence and importance of lipid rafts in cellular signaling by first understanding the initial signaling processes, and then disrupting the lipid rafts at which point they observe any changes in cellular function. Lipid rafts are typically disrupted by removing the cholesterol from the membrane, using systems such as cyclodextrin.

In normal B cells, when the cell encounters an antigen, the BCR shifts into a lipid raft domain and then relays a signal that causes the cell to proliferate into plasma cells and produce antibodies. However, when the cholesterol was depleted from B lymphocytes, presumably destroying lipid rafts, the BCRs were no longer able to relay the signal that they had encountered an antigen, and no antibodies were produced (Petrie et al, 2000). In a similar fashion, when rafts were depleted in T lymphocytes, the TCRs lost their ability to relay signals due to antigen attachment as well (Matko & Szollosi, 2002). Lipid raft depletion also affected the function of CD39 an enzyme that plays a role in platelet aggregation.

Rafts have been implicated in a hugh range of other processes and systems - signalling, molecular trafficking, diseases such as HIV and malaria as well as being involved in the immune, vasular, digestive and reproductive systems.

[edit] Visualization of lipid rafts

Due to their size being below the classical diffraction limit of the light microscope, lipid rafts have proved difficult to visualize directly. Despite this, fluorescence microscopy is used extensively in the field. For example, fluorophores conjugated to cholera-toxin B-subunit, which binds to the raft constituent ganglioside GM1 is used extensively. Also used are lipophilic membrane dyes which either partition between rafts and the bulk membrane, or change their fluorescent properties in response to membrane phase. Laurdan is one of the prime examples of such a dye. Rafts may also be labeled by genetic expression of fluorescent fusion proteins such as Lck-GFP. To combat the problems of small size and dynamic nature, single particle and molecule tracking using cooled, sensitive CCD cameras and total internal reflection (TIRF) microscopy is coming to prominence. This allows information of the diffusivity of particles in the membrane to be extracted as well as revealing membrane corrals, barriers and sites of confinement. The Kusumi lab are some of the leaders in this field of raft study. Other optical techniques are also used: Fluorescence Correlation and Cross-Correlation Spectroscopy (FCS/FCCS) can be used to gain information of fluorophore mobility in the membrane, Fluorescence Resonance Energy Transfer (FRET) can detect when fluorophores are in close proximity and optical tweezer techniques can give information on membrane viscosity. Also used are atomic force microscopy (AFM), Scanning Ion Conductance Microscopy (SICM), Nuclear Magnetic Resonance (NMR) although fluorescence microscopy remains the dominant technique. In the future it is hoped that super-resolution microscopy such as Stimulated Emission Depletion (STED) or various forms of structured illumination microscopy may overcome the problems imposed by the diffraction limit.

[edit] Controversy about lipid rafts

The evidence for lipid rafts is still a very controversial issue, and their role in cellular signaling, trafficking, and structure has yet to be determined despite many experiments involving several different methods. Arguments against the existence of lipid rafts include i) there should be a line tension between the Lα and Lo phases. Though this has been seen in model membranes, it has not been readily observed in cell systems, ii) the size of lipid rafts, this has been reported between 1 and 1000 nanometres, there seems to be no consensus, iii) timescale of the existence of lipid rafts. If they do exist they may only occurs on timescale irrelevant to biological processes. iv) the entire membrane may exist in the Lo phase. The rebuttal to this point suggests that the Lo phase of the rafts is more tightly packed due to the intermolecular hydrogen bonding exhibited between sphingolipids and cholesterol that is not seen elsewhere (Barenholz 2004). A second argument questions the effectiveness of the experimental design when disrupting lipid rafts. Pike and Miller (1998) discuss potential pitfalls of using cholesterol depletion as a method to determine lipid raft function. They noted that most researchers were using acute methods of cholesterol depletion, which not only disrupts the rafts, but also disrupts another lipid known as PIP(4,5)P2, which plays a large role in regulating the cell’s cytoskeleton (Caroni 2001). Kwik et al. (2002) found that disrupting PIP(4,5)P2 caused many of the same results as this type of cholesterol depletion, including lateral diffusion of the proteins in the membrane. Based on this, the authors concluded that loss of a particular cellular function after cholesterol depletion cannot necessarily be contributed solely to lipid raft disruption, as other processes independent of rafts may also be affected. Thirdly, while it is often agreed that proteins are in some way connected to lipid rafts, Edidin (2003) argues that it is the proteins that attract the lipids in the raft by means of the interactions of proteins with the acyl chains on the lipids, and not the other way around.

[edit] See also:

[edit] References

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