GPI-Anchored Proteins and Their Cellular Surroundings: Signalling, Function and Medical Implications of Membrane Microdomains

Sphingolipid- and cholesterol-rich membrane microdomains, often referred to as lipid rafts, harbour various plasma membrane proteins and can putatively provide a specific signalling platform for these proteins. Rafts were originally discovered as detergent-resistant lipid domains, but widely differing methods of isolation and analysis have led to numerous classifications, and there is still no coherence which further complicates the study of these domains. Subclasses of lipid rafts have been categorized depending on the specific lipid- and protein-composition, such as caveolae, raft-domains rich in caveolin proteins with tissue-specific signalling properties. Some lipid raft proteins are post-translationally modified by the covalent attachment of a glycosylphosphatidylinositol (GPI) anchor. The complexity of the GPI anchor implies a function beyond directing proteins to the plasma membrane, such as cell-cell communication, regulation of protein structure and cleavage, signal transduction and protein targeting. The mechanisms by which GPI-anchored outer membrane proteins may initiate intracellular signalling events are largely unknown; however several protein kinases have been implicated.

The importance of lipid microdomains becomes apparent in the raft localization of numerous proteins involved in the pathogenesis of diseases. These include neurological diseases such as Alzheimer’s and prion diseases, immunological diseases such as lupus erythematosus, and cardiovascular disease. Interestingly, the lipid composition of lipid rafts can be altered nutritionally, especially through dietary long chain fatty acids, which could potentially make lipid rafts an attractive pharmacological target.

Here we will analyze the signalling properties of lipid raft proteins and discuss their importance in health and disease.