Protein involvement in transmembrane lipid asymmetry.

Transmembrane asymmetry has been extensively studied in eukaryotic cells. It is as yet only clearly demonstrated in the plasma membrane of a few cells. Subcellular organelles have evidence of lipid asymmetry, but very little consistent quantitative data exist. Proteins involved in transmembrane passage of lipids comprise enzymes of lipid metabolism and also the so-called phospholipid flippases that are either passive or active putative lipid transporters. The aminophospholipid translocase that pumps amino-phospholipids from the outer to the inner monolayer of the plasma membrane of eukaryotes is a Mg(2+)-ATP dependent protein with a high lipid selectivity. Lipid asymmetry provides an asymmetrical environment for membrane enzymes. Thus, PS (and PE) reorientation could be a way of controlling or triggering specific enzymes. Also, the asymmetrical distribution of phospholipids most likely determines the fusion-competent membranes and/or which sides of membranes should fuse. Finally, the lipid pump as well as all enzymes responsible for the net transmembrane flux of phospholipids may provide the driving force for membrane bending, notably during the formation of endocytic vesicles. Clearly, real progress in this area will be made only if the proteins of the flippase family are purified and antibodies obtained that will permit the recognition and localization of these proteins in various cells. Also, specific inhibitors as well as mutants would allow one to infer more directly what are the real functions of these proteins. At a late stage, the protein purification will eventually permit speculation on the mechanism of action of a pump that must transport simultaneously hydrophilic and hydrophobic groups through a membrane.