The Journal of
© Springer-Verlag New York Inc. 1998
Structure and Origin of Ordered Lipid Domains in Biological Membranes
D.A. Brown, E. London
Department of Biochemistry and Cell Biology, Institute for Cell and Developmental Biology, State University of New York at Stony Brook, Stony Brook, NY 11794-5215, USAReceived: 26 January 1998/Revised: 9 March 1998
Introduction The clearest function of membrane lipids is to form amphipathic bilayers that surround cells and organelles and block leakage of hydrophilic compounds while housing membrane proteins. However, the wide variety of lipids observed in biological membranes would not be required for a simple barrier function. Phospholipids alone display avariety of headgroup and acyl chain structures, and eukaryotic cell membranes often contain sphingolipids and sterols as well. Functional consequences of this lipid heterogeneity are starting to emerge. One such consequence is the possibility of nonrandom mixing in the bilayer and the formation of lipid microdomains. It is clear that microdomains can form in artificial bilayers . However, despitemuch interest in the subject, convincing evidence that lipids can cluster in cell membranes has been slow to emerge. This review summarizes evidence that one type of microdomain may exist in cell membranes. Most of this evidence has come from studies of membrane fragments that are insoluble in cold non-ionic detergents such as Triton X-100. These detergent-resistant membranes (DRMs) are rich incholesterol and sphingolipids, and may exist in membranes in the liquid-ordered (lo) phase or a phase with similar properties. These studies may provide some of the first evidence for phase separation in biological membranes. Readers are also referred to our
recent reviews of DRMs and the ordered-domain model [5, 6], and to two other insightful reviews of these domains [8, 82]. Increasingevidence suggests that another type of domain, formed by electrostatic interactions between membrane-associated components, may exist in membranes . One intriguing example is the ability of a membrane-associated positively charged peptide derived from the MARCKS protein to organize domains rich in phosphatidylinositol bisphosphate . Though potentially very important, formation of these domainswill not be covered here. Lipids Can Undergo Phase Separation in Membranes; Description of the lo Phase Phospholipid bilayers usually exist in a ‘‘frozen,’’ ordered gel phase at low temperatures. Above a melting temperature (Tm) that is characteristic of each lipid, the bilayer is present in a phase, termed liquid-crystalline (lc) or liquid-disordered (ld), in which the lipid acyl chains are fluidand disordered. Binary mixtures of lipids with different Tm can be examined at temperatures between the Tm of the two lipids. When one component is present at low levels, the mixture is uniform, and generally remains in the phase favored by the major component. Above a threshold concentration of one component, cooperative phase separation occurs, and gel and lc phase domains coexist. Eukaryoticcell membranes contain mixtures of glycerolipids (in mammalian cells, all phospholipids except sphingomyelin), sphingolipids, and sterols. Biological glycerolipids generally have very low Tm, while sphingolipids (especially glycosphingolipids) have much
Correspondence to: D.A. Brown Key words: Liquid-ordered — Caveolae — GPI-anchored protein — Phase separation — DIG — Glycolipid raft
104D.A. Brown and E. London: Ordered Lipid Domains
Fig. 1. Temperature-composition phase diagram of the DPPCcholesterol system. Reproduced with permission from .
higher Tm. This disparity suggests that phase separation between glycerolipid- and sphingolipid-rich domains might occur. Consistent with this possibility, indications of glycosphingolipid clustering in the plasma membrane have...