One fundamental question in lipid biology concerns the generation, maintenance, and function of the asymmetric distribution of lipids within the leaflets of one membrane and the variation in lipid composition among the membranes of different organelles. What are the mechanisms underlying this complexity, and why is such complexity needed? We already know that certain lipids can specifically interact with and influence the activity of some proteins. For example, the large multimeric proteins that participate in oxidative phosphorylation in the inner mitochondrial membrane appear to assemble into supercomplexes whose stability may depend on the physical properties and binding of specialized phospholipids such as cardiolipin (see Chapter 12).

The existence of lipid rafts in biological membranes and their function in cell signaling remains a topic of heated debate. Many biochemical studies using model membranes show that stable lateral assemblies of sphingolipids and cholesterol—lipid rafts—can facilitate selective protein-protein interactions by excluding or including specific proteins. Whether or not lipid rafts exist in natural biomembranes, as well as their dimensions and dynamics, is under intense investigation. New biophysical and microscopic tools are beginning to provide a more solid basis for their existence, size, and behavior.

Despite considerable progress in our understanding of the cellular metabolism and movement of lipids, the mechanisms for transporting cholesterol and phospholipids between organelle membranes remain poorly characterized. In particular, we lack a detailed understanding of how various transport proteins move lipids from one membrane leaflet to another (flippase activity) and into and out of cells. Such understanding will require the determination of the structures of these molecules at high resolutions, their capture in various stages of the transport process, and careful kinetic and other biophysical analyses of their function, approaches similar to those discussed in Chapter 11 for elucidating the operation of ion channels and ATP-powered pumps.

Recent advances in solubilizing and crystallizing integral membrane proteins have led to the delineation of the molecular structures of many important types of proteins, such as ion channels, G protein–coupled receptors, ATP-powered ion pumps, the human GLUT1 glucose transporter, and aquaporins, as we will see in Chapter 11. However, many important classes of membrane proteins have proved recalcitrant to even these new approaches. As we will learn in Chapters 15 and 16, many classes of receptors span the plasma membrane with one or more α helices. Perhaps surprisingly, we lack the molecular structure of the transmembrane segment of any single-pass eukaryotic cell-surface receptor, so many aspects of the function of these proteins are still mysterious. The transmittal of information across the membrane that occurs when a single-pass receptor binds an appropriate ligand remains to be described at adequate molecular resolution. Elucidating the molecular structures of these and many other types of membrane proteins will clarify many aspects of molecular cell biology.