The challenge of lipid rafts

Abstract

The Singer-Nicholson model of membranes postulated a uniform lipid bilayer randomly studded with floating proteins. However, it became clear almost immediately that membranes were not uniform and that clusters of lipids in a more ordered state existed within the generally disorder lipid milieu of the membrane. These clusters of ordered lipids are now referred to as lipid rafts. This review summarizes current thinking on the nature of lipid rafts focusing on the role of proteomics and lipidomics in understanding the structure of these domains. It also outlines the contribution of single-molecule methods in defining the forces that drive the formation and dynamics of these membrane domains.-Pike, L. J. A major step forward in our understanding of the structure of biological membranes was the publication by Singer and Nicolson (1) in 1972 of the fluid mosaic model of membranes. The model described the membrane as a primarily lipid matrix with randomly distributed proteins. The ink had barely dried on this landmark paper before experimental evidence was obtained that suggested that the uniformly random distribution of proteins and lipids envisioned by Singer and Nicholson was probably inaccurate. By 1974, studies on the effects of temperature on membrane behavior had led investigators to propose the presence of "clusters of lipids" in membranes (2), and by the following year data were obtained that suggested that these clusters might be "quasicrystalline" regions surrounded by more freely dispersed liquid crystalline lipid molecules (3). By 1978, this idea had been refined from "rigid liquid crystalline" clusters to "lipids in a more ordered state" (4).The concept of lipid domains in membranes was formalized in 1982 by Karnovsky et al. (5), who observed heterogeneity in the lifetime decay of 1,6-diphenyl-1,3,5-hexatriene, indicating multiple phases in the lipid environment of the membrane. These workers also investigated the functional effect of altering membrane structure by the addition of specific fatty acids, and presciently, by the depletion of cholesterol. They closed their manuscript with a series of questions that were raised by the "concept of the organization of the lipid components of membranes into domains." Their questions are worth reiterating because almost 3 decades later they remain major challenges in the study of the structures that we have come to call lipid rafts. 1) Do specific membrane proteins reside in specific lipid domains, and can perturbation of the specific domain structure affect protein structure and function? 2) Do lipophilic molecules and drugs preferentially partition and segregate into specific domains rather than into a bulk lipid phase, and may such unique partitioning predicate specific functional effects? 3) What forces underlie the formation, maintenance, and fluctuation of lipid domains? 4) Because the very concept of domains implies domain boundaries or interfaces, what is the possible biological significance of such interfaces?In this review, I will summarize rece...

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