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Membrane Lipids: Where They Are and How They Behave

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REVIEWS Membrane lipids: where they are and how they behave Gerrit van Meer*, Dennis R. Voelker‡ and Gerald W. Feigenson§ Abstract | Throughout the biological world, a 30 Å hydrophobic film typically delimits the environments that serve as the margin between life and death for individual cells. Biochemical and biophysical findings have provided a detailed model of the composition and structure of membranes, which includes levels of dynamic organization both across the lipid bilayer (lipid asymmetry) and in the lateral dimension (lipid domains) of membranes. How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functionalities of their individual membranes? Triacylglycerol From the ongoing cataloguing of lipid structures (lipid- fission and fusion, characteristics that are essential for A family of storage lipids omics), it is clear that eukaryotic cells invest substantial cell division, biological reproduction and intracellular consisting of glycerol esterified resources in generating thousands of different lipids1. Why membrane trafficking. Lipids also allow particular pro- to three fatty acids, forming the do cells use ~5% of their genes to synthesize all of these teins in membranes to aggregate, and others to disperse. hydrophobic core of lipid droplets and blood lipids? The fundamental biological maxim that ‘structure Finally, lipids can act as first and second messengers in lipoproteins together with subserves function’ implies that there must be evolution- signal transduction and molecular recognition processes. steryl esters. ary advantages that are dependent on a complex lipid The degradation of amphipathic lipids allows for bipartite repertoire. Although we now understand the specific func- signalling phenomena, which can be transmitted within Steryl ester A family of storage lipids tions of numerous lipids, the full definition of the utility a membrane by hydrophobic portions of the molecule consisting of sterol esterified of the eukaryotic lipid repertoire remains elusive. and also propagated through the cytosol by soluble to one fatty acid, forming the Lipids fulfil three general functions. First, because of (polar) portions of the molecule. In addition, some lipids hydrophobic core of lipid their relatively reduced state, lipids are used for energy function to define membrane domains, which recruit droplets and blood storage, principally as triacylglycerol and steryl esters, in proteins from the cytosol that subsequently organize lipoproteins together with triacylglycerol molecules. lipid droplets. These function primarily as anhydrous secondary signalling or effector complexes. reservoirs for the efficient storage of caloric reserves and Progress in biophysics, chemistry and genetics has Amphipathic as caches of fatty acid and sterol components that are attracted renewed attention to the biological roles of the The characteristic of being needed for membrane biogenesis. Second, the matrix great variety of membrane lipids. One property of lipids polar on one side of the molecule and apolar on of cellular membranes is formed by polar lipids, which that has fascinated scientists is their phase behaviour. In the opposite side. consist of a hydrophobic and a hydrophilic portion. The cells, lipids can adopt various fluid and solid phases, which propensity of the hydrophobic moieties to self-associate are characterized by a different spatial arrangement and (entropically driven by water), and the tendency of the motional freedom of each lipid with respect to its neigh- *Bijvoet Center and Institute of Biomembranes, Utrecht hydrophilic moieties to interact with aqueous environ- bours. Biophysical approaches have defined the principles University, 3584 CH Utrecht, ments and with each other, is the physical basis of the of coexistence of two fluid phases (with different physical The Netherlands. spontaneous formation of membranes. This fundamental characteristics within a single membrane plane) that are ‡Department of Medicine, principle of amphipathic lipids is a chemical property that delimited by a phase boundary, and the consequences on National Jewish Medical 2,3 Research Center, Denver, enabled the first cells to segregate their internal constitu- membrane organization . Advances in mass spectrom- Colorado 80206, USA. ents from the external environment. This same principle is etry have catalysed precipitous developments in holistic, §Department of Molecular recapitulated within the cell to produce discrete organelles. high-sensitivity (and high-throughput) lipid analysis, Biology and Genetics, Cornell This compartmentalization enables segregation of specific welcoming lipids to the realm of genomics and proteom- University, Ithaca, New York chemical reactions for the purposes of increased biochem- ics1. The identification of new disease-related genes has 14853, USA. Correspondence to G.v.M. ical efficiency and restricted dissemination of reaction revealed the involvement of lipid-related proteins, such e-mail: [email protected] products. In addition to the barrier function, lipids provide as enzymes (lysosomal hydrolases), transporters (ATP- doi:10.1038/nrm2330 membranes with the potential for budding, tubulation, binding cassette (ABC) transporters) or lipid binding 112 | FEBRUARY 2008 | VolUME 9 www.nature.com/reviews/molcellbio © 2008 Nature Publishing Group FOCUS ONREVIEWS LIPIDS Structural Signalling O O O O PC P LPC LPA O O O O O P P + CH N 3 O O O OH + CH O O OH O CH3 N 3 CH3 OH OH OH CH3 OH CH3 O AA OH Eicosanoids O DAG O O OH PA O O P O O O OH O OH O O SM S1P OH O OH O SPC OH O P P P O OH O O O O + CH3 + CH3 OH OH N OH N NH2 NH CH3 NH2 CH3 CH3 CH3 O Sph OH C1P OH O OH P NH2 O OH NH OH Cer OH O GlcCer OH OH OH NH HO OH O O NH OH O O O O PI PIP O O PIP PIP2 3 P P OH OH P OH HO OH HO P O O O OH O O O P OH O O OH O O OH Cholesterol Figure 1 | Membrane lipids and lipid second messengers. The main is amide-linked to a fatty acid. Yeast sphingolipids carry a C26 fatty acid and eukaryotic membrane lipids are the glycerophospholipids such as have phosphoinositol-X substituents that contain additional mannoses and Nature Reviews | Molecular Cell Biology phosphatidylcholine (PtdCho; PC). Their diacylglycerol (DAG) backbone phosphates. Breakdown products of membrane lipids serve as lipid second carries a phosphate (phosphatidic acid; PA) esterified to either a choline messengers. The glycerolipid-derived signalling molecules include (forming PtdCho), ethanolamine (forming phosphatidylethanolamine lysoPtdCho (LPC), lysoPA (LPA), PA and DAG. The sphingolipid-derived (PtdEtn); not shown), serine (forming phosphatidylserine (PtdSer); not signalling molecules include sphingosylphosphorylcholine (SPC), Sph, shown), or inositol (forming phosphatidylinositol (PtdIns); PI). The prototypical sphingosine-1-phosphate (S1P), Cer-1-phosphate (C1P) and Cer. Arachidonic phospholipid, dipalmitoyl-PtdCho, exhibits nearly cylindrical molecular acid (AA) yields the signalling eicosanoids and endocannabinoids (not shown). geometry with a cross-sectional surface area of 64 Å2 and a head-to-tail The various phosphorylated PtdIns molecules (PIPs; also known as the length of 19 Å (REF. 122). The phosphosphingolipid sphingomyelin (SM) and phosphoinositides) mark cellular membranes and recruit cytosolic proteins. the glycosphingolipid glucosylceramide (GlcCer) have a ceramide (Cer) They are interconverted by the actions of kinases and phosphatases. backbone, consisting of a sphingoid base (such as sphingosine; Sph), which Fig. modified with permission from REF. 5 (2005) Macmillan Publishers Ltd. NatURE REVIEws | MOLECULAR CELL BIOLOGY VolUME 9 | FEBRUARY 2008 | 113 © 2008 Nature Publishing Group REVIEWS proteins (START domain proteins). It is now essential sphingolipids is caused by shielding of the non-polar to define the molecular function of the corresponding sterol by the sphingolipid headgroup rather than being gene products to improve diagnostics and develop cures caused by preferential intermolecular interactions (see for the respective diseases. Pathological processes such as the review by Ikonen in this issue). viral infection have been unexpectedly connected to spe- Signalling-induced hydrolysis of glycerolipids and cific membrane lipids and their biophysical properties4, sphingolipids produces parallel series of messenger lipids: emphasizing the need for an integrated study of cellular lysoPtdCho (LPC), lysoPA (LPA), PA and DAG, versus lipids using lipidomic methods5. sphingosylphosphorylcholine (SPC), sphingosine (Sph), Here, we introduce the main lipids of biomembranes, sphingosine-1-phosphate (S1P), ceramide-1-phosphate their topology and the spatial organization of their (C1P) and Cer (FIG. 1). LPC, LPA, SPC, Sph and S1P carry metabolism. We emphasize how metabolism and selective only one aliphatic chain and readily leave membranes; they transport maintain the differences in lipid composition signal through related membrane receptors11. By contrast, between organelles, and highlight how the biophysical PA, DAG, C1P and Cer remain in the membrane and can properties of the different lipids and their phase behaviour recruit cytosolic proteins12. Interestingly, when signalling contribute to membrane function. We discuss mammalian lipids such as Cer are generated in large quantities13,14, they cells and yeast to highlight similarities, and demonstrate can
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