Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts)

Ordered lipid domains enriched in sphingolipids and cholesterol (lipid raft s) have been implicated in numerous functions in biological membranes. We r ecently found that lipid domain/raft formation is dependent on the sterol c omponent having a structure that allows tight packing with lipids having sa turated acyl chains (Xu, X., and London, E. (2000) Biochemistry 39, 844-849 ). In this study, the domain-promoting activities of various natural sterol s were compared with that of cholesterol using both fluorescence quenching and detergent insolubility methods. Using model membranes, it was shown tha t, like cholesterol, both plant and fungal sterols promote the formation of tightly packed, ordered lipid domains by lipids with saturated acyl chains . Surprisingly ergosterol, a fungal sterol, and 7-dehydrocholesterol, a ste rol present in elevated levels in Smith-Lemli-Opitz syndrome, were both sig nificantly more strongly domain-promoting than cholesterol. Domain formatio n was also affected by the structure of the sphingolipid (or that of an equ ivalent "saturated" phospholipid) component. Sterols had pronounced effects on domain formation by sphingomyelin and dipalmitoylphosphatidyleholine bu t only a weak influence on the ability of cerebrosides to form domains. Str ikingly it was found that a small amount of ceramide (3 mol %) significantl y stabilized domain/raft format-ion. The molecular basis for, and the impli cations of, the effects of different sterols and sphingolipids (especially ceramide) on the behavior and biological function of rafts are discussed.