The Lipid Whisker Model of the Structure of Oxidized Cell Membranes

Abstract

An essential feature of the innate immune system is maintaining cellular homeostasis by identifying and removing senescent and apoptotic cells and modified lipoproteins. Identification is achieved through the recognition of molecular patterns, including structurally distinct oxidized phospholipids, on target cells by macrophage receptors. Both the structural nature of the molecular patterns recognized and their orientation within membranes has remained elusive. We recently described the membrane conformation of an endogenous oxidized phospholipid ligand for macrophage scavenger receptor CD36, where the truncated oxidized sn-2 fatty acid moiety protrudes into the aqueous phase, rendering it accessible for recognition. Herein we examine the generality of this conformational motif for peroxidized glycerophospholipids within membranes. Our data reveal that the addition of a polar oxygen atom on numerous peroxidized fatty acids reorients the acyl chain, whereby it no longer remains buried within the membrane interior but rather protrudes into the aqueous compartment. Moreover, we show that neither a conformational change in the head group relative to the membrane surface nor the presence of a polar head group is essential for CD36 recognition of free oxidized phospholipid ligands within membranes. Rather, our results suggest the following global phenomenon. As cellular membranes undergo lipid peroxidation, such as during senescence or apoptosis, previously hydrophobic portions of fatty acids will move from the interior of the lipid bilayer to the aqueous exterior. This enables physical contact between pattern recognition receptor and molecular pattern ligand. Cell membranes thus "grow whiskers" as phospholipids undergo peroxidation, and many of their oxidized fatty acids protrude at the surface.The fluid mosaic model of membrane architecture, first proposed by Singer and Nicolson (1), is a cornerstone of cell biology. An integral feature of this model is the macromolecular assembly of amphipathic phospholipids into a bilayer structure, with polar head groups directed toward the aqueous phase and hydrophobic aliphatic fatty acid chains of glycerophospholipids extending toward the membrane interior. The bilayer structure posited explains how a cell membrane maintains a critical barrier function while it simultaneously facilitates rapid lateral diffusion of proteins and lipids within the planar membrane surface.Some biological processes, however, are not compatible with a classic phospholipid orientation as described for a lamellar (bilayer) phase membrane structure and instead involve alternative phospholipid conformations. For example, membrane fusion of two vesicles must be accompanied by a transient nonlamellar phase orientation of the phospholipids at the site of membrane fusion (2, 3). Perhaps less obvious is the recognition of a phospholipid ligand within a membrane bilayer of one cell by an alternative cell's receptor. It is hard to envision how a macrophage pattern recognition receptor like CD36 can identify se...

Oxidized Phospholipids as Endogenous Pattern Recognition Ligands in Innate Immunity

“…The structures of oxPC CD36 identified were established using a combination of cell binding studies and multiple distinct chromatographic and MS methods in conjunction with (i) results of numerous derivatization strategies to ascertain functional groups on isolated products, (ii) inference of structures of products that appeared plausible based upon MS results and known mechanisms of lipid oxidation and fragmentation, and (iii) de novo synthesis of each oxidized lipid. The identities of the oxidation products and synthetic standards were confirmed by demonstration that synthetic species recapitulate all biological, chemical, MS, and chromatographic characteristics of the lipids isolated from oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-PC, oxidized 1-palmitoyl-2-lineoyl-sn-glycero-3-PC, and oxidized 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-PC (19,20,22,40,41). Liquid chromatographic/electrospray ionization/tandem MS analyses have demonstrated the generation of these species in lipoproteins oxidized by multiple distinct pathways in vitro (40), in atherosclerotic lesions in vivo (41), in retina following light exposure in dark-adapted rodents (20), and in cerebral tissues following ischemia-reperfusion injury (42).…”

“…Although initially defined using PC molecular species, as outlined below, subsequent studies have shown that all classes of phospholipids examined thus far (PC, phosphatidylethanolamine, PS, and phosphatidic acid) harboring the high affinity motif for CD36 promote CD36-mediated recognition and phagocytosis (19,20,22,40,41). The structures of oxPC CD36 identified were established using a combination of cell binding studies and multiple distinct chromatographic and MS methods in conjunction with (i) results of numerous derivatization strategies to ascertain functional groups on isolated products, (ii) inference of structures of products that appeared plausible based upon MS results and known mechanisms of lipid oxidation and fragmentation, and (iii) de novo synthesis of each oxidized lipid.…”

“…This review will discuss recent discoveries regarding the structural nature of oxidized phospholipids that serve as high affinity ligands for CD36 in vivo. Also discussed will be the Lipid Whisker Model (22). A revision to the Fluid Mosaic Model (23), the Lipid Whisker Model focuses on phospholipid conformation within oxidized cell membranes and lipoproteins and is derived from recent studies demonstrating the generality of a conformational switch in the structure of many phospholipids within cell membranes that occurs following oxidation.…”

“…A revision to the Fluid Mosaic Model (23), the Lipid Whisker Model focuses on phospholipid conformation within oxidized cell membranes and lipoproteins and is derived from recent studies demonstrating the generality of a conformational switch in the structure of many phospholipids within cell membranes that occurs following oxidation. The conformational switch, involving the protrusion of oxidized fatty acids from the hydrophobic membrane interior into the more polar aqueous compartment (22,24), facilitates physical contact between pattern recognition receptor and molecular pattern ligand. This anatomic positioning of oxidized fatty acids of membrane phospholipids may also underlie the preferential selectivity of some phospholipases for oxidized fatty acids during membrane remodeling.…”

Cochorous olitorous and Adasonia digitata leaves extracts protects against gamma radiation induced anaemia

“…These reactive species react with the biomolecules such as nucleic acids (DNA and RNA), mostly membrane proteins and lipids, resulting to chain of reaction leading to lipid peroxidation, protein oxidation and Nucleic acid-base breakage (Parihar et al, 2007). ROS in membranes could cause alterations to the integrity, fluidity, permeability and biological functions of membranes; while they could generate in low density lipoprotein (LDL) proatherogenic and proinflammatory response as well as generates toxic products (Greenberg et al, 2008). One of the pathological conditions resulting from human exposure to radiations is anaemia, a blood disorder which affects all age groups especially the elderly, pregnant, lactating women and infants been more susceptible.…”