How proteins move lipids and lipids move proteins

Cellular membranes have distinct compositions that reflect their unique functions. Membrane proteins, synthesized in the cytosol or at the endoplasmic reticulum (ER) membrane, are targeted to the different membranes by structural motifs. Local lipid synthesis and hydrolysis cannot explain the differences in lipid composition between the various membranes and between the two leaflets of the bilayer. The intracellular transport of lipids is selective. Lipids are transported as monomers across membranes. Various families of transporters have been identified that might provide the necessary directionality and lipid specificity. The main transport mechanism for lipids and proteins between organelles is vesicular. Selectivity in these pathways is generated by the lateral segregation of anterograde from retrograde (or resident) components. Lipid sorting is based on a spontaneous phase separation into less fluid sphingolipid–cholesterol domains, that move towards the plasma membrane, and more fluid glycerophospholipid domains, that are preferentially included in transport vesicles towards the ER. Special properties of the lipid domains are recognized by various classes of membrane protein. Some of these are cargo being sorted, others provide directionality to the resulting transport vesicles. Topologically and temporally restricted metabolism of lipids modifies their molecular shape. This seems to be an integral part of vesicle fission and, potentially, fusion. The local production of signalling lipids determines membrane flux by coat recruitment and the activation of fusion. The activity of the responsible enzymes — kinases, phosphatases and phospholipases — is subject to regulation and forms an integral part of the cellular signalling system.