Rafts, little caves and large potholes: how lipid structure interacts with membrane proteins to create functionally...

This chapter reviews how diverse lipid microdomains form in the membrane and partition proteins into different functional units that regulate cell trafficking, signalling and movement. We will concentrate upon five major issues: 1. the diversity of lipid structure that produces diverse microenvironments into which different subsets of proteins partition; 2. why ordered lipid domains exclude proteins, and the conditions required for select subsets of proteins to enter these domains; 3. the coupling of the inner and outer leaflets within ordered microdomains; 4. the effect of ordered lipid domains upon membrane properties including curvature and hydrophobicity that affect membrane fission, fusion and extension of filopodia; 5. the biological effects of these structural constraints; in particular how the properties of these domains combine to provide a very different signalling, trafficking and membrane fusion environment to that found in disordered (fluid mosaic) membrane. In addressing these problems, the review draws upon studies ranging from molecular dynamic modelling of lipid interactions, through physical studies of model membrane systems to structural and biological studies of whole cells, examining in the process problems inherent in visualising and purifying these microdomains. While the diversity of structure and function of ordered lipid microdomains is emphasised, some general roles emerge. In particular, the basis for having quite different, non-interacting ordered lipid domains on the same membrane is evident in the diversity of lipid structure and plays a key role in sorting signalling systems. The exclusion of ordered membrane from coated pits, and hence rapid endocytosis, is suggested to underlie the ability of highly ordered domains to establish stable secondary signalling systems required, for instance, in T cell receptor, insulin and neurotrophin signalling.