Controlling Membrane Cholesterol Content. A Role for Polyunsaturated (Docosahexaenoate) Phospholipids

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Abstract
The molecular organization of cholesterol in 1,2-didocosahexaenoylphosphatidylcholine (22:6-22:6PC) and 1-stearoyl-2-docosahexaenoylphosphatidylcholine (18:0-22:6PC) bilayers was investigated. Using low- and wide-angle X-ray diffraction (XRD), we determined that the solubility of the sterol at 20 °C was 11 ± 3 mol % in 22:6-22:6PC vs 55 ± 3 mol % in 18:0-22:6PC bilayers. Solubility in the dipolyunsaturated membrane rose to 17 ± 3 mol % at 40 °C, while in the saturated−polyunsaturated membrane there was no change within experimental uncertainty. We compared the molecular orientation of [3α-2H1]cholesterol incorporated into 22:6-22:6PC bilayers to its solubility limit and into 18:0-22:6PC bilayers to a comparable concentration (10 mol %) in solid-state 2H NMR experiments. The sterol possessed a tilt angle α0 = 24° ± 1° in 22:6-22:6PC that was independent of temperature over a range from 20 to 40 °C. In contrast, the value was α0 = 21° ± 1° in 18:0-22:6 bilayers at 20 °C and increased to α0 = 24° ± 1° at 40 °C. We attribute the low solubility of cholesterol in 22:6-22:6PC membranes to steric incompatibility between the rigid steroid moiety and the highly disordered docosahexaenoic acid (DHA) chain, which has the potential to promote lateral heterogeneity within DHA-rich membranes. Considering 22:6-22:6PC to be the most unsaturated phospholipid found in vivo, this model membrane study provides a point of reference for elucidating the role of sterol−lipid interactions in controlling local compositional organization. Our results form the basis for a model that is consistent with cholesterol's ability to modulate the activity of certain neural transmembrane proteins.