Sphingolipid organization in biomembranes: what physical studies of model membranes reveal

Abstract

Recent cell biological studies suggest that sphingolipids and cholesterol may cluster in biomembranes to form raft-like microdomains. Such lipid domains are postulated to function as platforms involved in the lateral sorting of certain proteins during their trafficking within cells as well as during signal transduction events. Here, the physical interactions that occur between cholesterol and sphingolipids in model membrane systems are discussed within the context of microdomain formation. A model is presented in which the role of cholesterol is refined compared to earlier models.

Fig. 1

Schematic portraying the molecular arrangement of the glycosphingolipid, asialo-GM1, in a liquid-crystalline PC matrix. One half of the bilayer is depicted. Asialo-GM1 is denoted by the filled tetramerically linked hexagons which represent the four uncharged sugar residues of this glycolipid. The effect of cholesterol on the clustering of asialo-GM1 was not considered. (Adapted from Thompson et al. (1986), copyright 1986, Plenum Publishing Corp.)

Fig. 2

Structural features of typical sphingolipids, cholesterol, and phosphoglycerides. (Sphingomyelin = SM; galactosylceramide = GalCer; glycerophosphocholine = PC; methyl groups in cholesterol = Me). For simplicity, the hydrocarbon chains of the lipids are depicted as fully extended trans rotamers. In reality, free rotation about the carbon-carbon single bonds provides numerous trans-gauche isomers in the fluid but not the gel state. The cis double bond depicted in the sn-2 chain of PC leads to a t⁺gt⁻ kink. Rotation about nearby carbon-carbon bonds increases the average molecular cross-sectional area. In PC, the glycerol base chain is depicted in gray and the highly hydratable, zwitterionic phosphorylcholine headgroup is depicted as a shaded ellipse oriented roughly parallel to the bilayer surface. In SM, the phosphorylcholine headgroup is depicted similarly and a stearoyl (18:0) acyl chain, typical of bovine brain SM, is shown amide-linked to the 18-carbon sphingosine base. In GalCer, the uncharged and lowly hydratable galactose headgroup is depicted as an unfilled circle, whereas, a lignoceroyl (24:0) acyl chain, typical of bovine brain GalCer, is shown amide-linked to the 18-carbon sphingosine base. In cholesterol, the 3-OH group as well as the methyl (Me) groups at positions 18,19, 21, and 26 all protrude from the β face of the molecule (see Bittman, 1997, for more detail).