Cholesterol and Sphingolipids Cluster with Specific Proteins in Membrane Microdomains

The results of recent studies have challenged the long-held belief that lipids are randomly mixed in each leaflet of a bi-layer. The first hint that lipids may be organized within the leaflets was the discovery that the residues remaining after the extraction of plasma membranes with detergents contain two lipids: cholesterol and sphingomyelin. Because these two lipids are found in more ordered, less fluid bilayers, researchers hypothesized that they form microdomains, termed lipid rafts, surrounded by other more fluid phospholipids that are easily extracted by detergents.

Biochemical and microscopic evidence supports the existence of lipid rafts in natural membranes. For instance, fluorescence microscopy reveals aggregates of lipids and raft-specific proteins in the membrane (Figure 5-10). The rafts are heterogeneous in size but are typically 50 nm in diameter. Rafts can be disrupted by methyl-^-cyclodextrin, which depletes the membrane of cholesterol, or by antibiotics, such as filipin, that sequester cholesterol; such findings indicate the importance of cholesterol in maintaining the molecules of the protein that It recognizes. Cross-linking causes the proteins or lipids to form larger patches that can be detected by fluorescence microscopy (see Figure 5-42). (a) Micrograph of a cell treated with toxin and with anti-PLAP antibody shows GM1 and PLAP colocalized in the same patches (yellow). This copatching suggests that both GM1 and PLAP are present in lipid rafts that coalesce in the presence of the cross-linking reagents. (b) Micrograph of a cell treated with toxin and with anti-TfR antibody shows that GM1 and TfR reside in separate patches (i.e., red and green), indicating that TfR is not a raft-resident protein. [Micrographs from T Harder et al., 1998, J. Cell Biol. 141:929.]

integrity of these rafts. Besides their enrichment by cholesterol and sphingolipids, lipid rafts are enriched for many types of cell-surface receptor proteins, as well as many signaling proteins that bind to the receptors and are activated by them. These lipid-protein complexes can form only in the two-dimensional environment of a hydrophobic bilayer and, as discussed in later chapters, they are thought to facilitate the detection of chemical signals from the external environment and the subsequent activation of cytosolic events.

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