Above: Computer simulation of a retroviral protein interacting with a lipid membrane (image credit Milka Doktorova and Jill Hemman).

The interaction of a living cell with the outside world is mediated by a thin layer of lipids and associated proteins called the plasma membrane.

Just two lipid molecules thick, this oily sheet was long thought to be a simple barrier that protects a cell from its surroundings, providing structural integrity and enabling a regulated internal environment necessary for life's chemical reactions. However, new research is upending this simplistic viewpoint and replacing it with a more complicated one, in which the three-dimensional organization of hundreds of chemically distinct lipids and thousands of unique proteins plays an active role in the life of a cell.

The current model for lateral organization of the plasma membrane (figure from  Sezgin et al. 2017 Nat. Rev. Mol. Cell Biol. 18:361 ).

The current model for lateral organization of the plasma membrane (figure from Sezgin et al. 2017 Nat. Rev. Mol. Cell Biol. 18:361).

As this new picture of membrane organization slowly comes into focus, a general consensus has emerged: within the outer leaflet of the mammalian plasma membrane, saturated lipids (including sphingomyelins) and cholesterol segregate from more disordered unsaturated lipids to form transient clusters, akin to tiny rafts floating in a vast sea. (The analogy is so compelling that the first researchers to clearly state and formalize this model for membrane organization called it the “lipid raft hypothesis”!) Now almost 20 years later, an abundance of biochemical evidence suggests a role for these microdomains in diverse membrane functions, both normal and pathological. For example, given the right external signal, rafts can be induced to coalesce into larger structures that in turn influence the lateral organization of transmembrane proteins, leading to changes in the internal chemistry of the cell. Our lab uses biophysical methods to understand how the different types of lipids found in cell membranes influence raft formation and properties such as composition, size, and morphology. Learn more about our research into rafts.

Orthogonal to the in-plane plasma membrane structure, cells constantly work to sort different classes of lipids between the inner and outer halves of the bilayer, resulting in two leaflets with different physical and chemical properties. It is not clear how a healthy cell utilizes this asymmetry in its normal life, but valuable energy is used to maintain it, and disruption of the asymmetry rapidly leads to cell death by phagocytosis. Despite intense interest, the fundamental principles underlying communication between leaflets of different composition remain elusive. Learn more about our efforts to prepare asymmetric model membranes and measure their structure.