title: Controlling membrane cholesterol content. A role for polyunsaturated (docosahexaenoate) phospholipids.
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 degrees 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 degrees C, while in the saturated-polyunsaturated membrane there was no change within experimental uncertainty. We compared the molecular orientation of [3alpha-(2)H(1)]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 (2)H NMR experiments. The sterol possessed a tilt angle alpha(0) = 24 degrees +/- 1 degrees in 22:6-22:6PC that was independent of temperature over a range from 20 to 40 degrees C. In contrast, the value was alpha(0) = 21 degrees +/- 1 degrees in 18:0-22:6 bilayers at 20 degrees C and increased to alpha(0) = 24 degrees +/- 1 degrees at 40 degrees 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.
mesh_terms: D002784:Cholesterol / Q000737:chemistry*; D003903:Deuterium / Q000737:chemistry; D004281:Docosahexaenoic Acids / Q000737:chemistry*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry*; D021962:Membrane Microdomains / Q000737:chemistry; D008956:Models, Chemical; D019906:Nuclear Magnetic Resonance, Biomolecular; D010713:Phosphatidylcholines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry*; D010759:Phosphorus Isotopes; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: C409542:1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine; D005231:Fatty Acids, Unsaturated; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010743:Phospholipids; D010759:Phosphorus Isotopes; C417741:didocosahexaenoylphosphatidylcholine; D004281:Docosahexaenoic Acids; D002784:Cholesterol; D003903:Deuterium