Ablation of ceramide synthase 2 strongly affects biophysical properties of membranes (original) (raw)
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Effects of ceramide and other simple sphingolipids on membrane lateral structure
Biochimica Et Biophysica Acta-biomembranes, 2009
The available data concerning the ability of ceramide and other simple sphingolipids to segregate laterally into rigid, gel-like domains in a fluid bilayer has been reviewed. Ceramides give rise to rigid ceramideenriched domains when their N-acyl chain is longer than C12. The high melting temperature of hydrated ceramides, revealing a tight intermolecular interaction, is probably responsible for their lateral segregation. Ceramides compete with cholesterol for the formation of domains with lipids such as sphingomyelin or saturated phosphatidylcholines; under these conditions displacement of cholesterol by ceramide involves a transition from a liquid-ordered to a gel-like phase in the domains involved. When ceramide is generated in situ by a sphingomyelinase, instead of being premixed with the other lipids, gel-like domain formation occurs as well, although the topology of the domains may not be the same, the enzyme causing clustering of domains that is not detected with premixed ceramide. Ceramide-1-phosphate is not likely to form domains in fluid bilayers, and the same is true of sphingosine and of sphingosine-1-phosphate. However, sphingosine does rigidify pre-existing gel domains in mixed bilayers.
Ceramide and Other Sphingolipids in Cellular Responses
Cell Biochemistry and Biophysics, 2004
Our knowledge of the structure and function of sphingolipids (sphingoid-based lipids) has expanded dramatically in recent years. Sphingolipids were first recognized-and named-more than 100 yrs ago by J. L. W. Thudichum, and were initially regarded as antigens, tumor markers, or as receptors for viral and bacterial products. As structural elements, sphingolipids and cholesterol were also found to form rafts (also called detergent-insoluble glycolipid-enriched complexes, detergentresistant membranes, Triton-insoluble floating fractions, glycolipid-enriched membranes, or microdomains) on eukaryotic membranes that function as platforms for the attachment of
Ceramide-containing membranes: The interface between biophysics and biology
Trends in Glycoscience and Glycotechnology, 2008
Sphingolipids are important constituents of biological membranes. Ceramide, the major metabolite of this family, is involved in many cellular processes, ranging from diŠerentiation to senescence and apoptosis. Ceramide is an amphipathic molecule with a small head group that allows it to be more promiscuous within membranes than other lipids. Ceramide has a strong ability to change the physical properties of membranes through the formation of ceramide-rich domains, whose physical and morphological characteristics can be studied by a variety of biophysical techniques. While the existence of lipid domains is widely accepted, data from the literature is not consistent concerning many of their properties. We now discuss the biophysical and biological signiˆcance of two types of membrane domains (lipid rafts and ceramidedomains). In addition, we discuss other properties of ceramide, such as its ability to permeabilize the outer membrane of mitochondria. Finally, we attempt to integrate these various issues from biochemical and biophysical perspectives.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2011
Ceramide is an important bioactive sphingolipid involved in a variety of biological processes. The mechanisms by which ceramide regulates biological events are not fully understood, but may involve alterations in the biophysical properties of membranes. We now examine the properties of ceramide with different acyl chains including long chain (C16-and C18-), very long chain (C24-) and unsaturated (C18:1-and C24:1-) ceramides, in phosphatidylcholine model membranes. Our results show that i) saturated ceramides have a stronger impact on the fluid membrane, increasing its order and promoting gel/fluid phase separation, while their unsaturated counterparts have a lower (C24:1-) or no (C18:1-) ability to form gel domains at 37°C; ii) differences between saturated species are smaller and are mainly related to the morphology and size of the gel domains, and iii) very long chain ceramides form tubular structures likely due to their ability to form interdigitated phases. These results suggest that generation of different ceramide species in cell membranes has a distinct biophysical impact with acyl chain saturation dictating membrane lateral organization, and chain asymmetry governing interdigitation and membrane morphology.
Characterization of Ceramide Synthase 2
Journal of Biological Chemistry, 2007
Ceramide is an important lipid signaling molecule and a key intermediate in sphingolipid biosynthesis. Recent studies have implied a previously unappreciated role for the ceramide N-acyl chain length, inasmuch as ceramides containing specific fatty acids appear to play defined roles in cell physiology. The discovery of a family of mammalian ceramide synthases (CerS), each of which utilizes a restricted subset of acyl-CoAs for ceramide synthesis, strengthens this notion. We now report the characterization of mammalian CerS2. qPCR analysis reveals that CerS2 mRNA is found at the highest level of all CerS and has the broadest tissue distribution. CerS2 has a remarkable acyl-CoA specificity, showing no activity using C16:0-CoA and very low activity using C18:0, rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis. There is a good correlation between CerS2 mRNA levels and levels of ceramide and sphingomyelin containing long acyl chains, at least in tissues where CerS2 mRNA is expressed at high levels. Interestingly, the activity of CerS2 can be regulated by another bioactive sphingolipid, sphingosine 1-phosphate (S1P), via interaction of S1P with two residues that are part of an S1P receptor-like motif found only in CerS2. These findings provide insight into the biochemical basis for the ceramide N-acyl chain composition of cells, and also reveal a novel and potentially important interplay between two bioactive sphingolipids that could be relevant to the regulation of sphingolipid metabolism and the opposing functions that these lipids play in signaling pathways.
Membrane microdomains: Role of ceramides in the maintenance of their structure and functions
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2009
Free-standing giant unilamellar vesicles were used to visualize the complex lateral heterogeneity, induced by ceramide in the membrane bilayer at micron scale using C 12 -NBD-PC probe partitioning under the fluorescence microscope. Ceramide gel domains exist as leaf-like structures in glycerophospholipid/ceramide mixtures. Cholesterol readily increases ceramide miscibility with glycerophospholipids but cholesterolceramide interactions are not involved in the organization of the liquid-ordered phase as exemplified by sphingomyelin/cholesterol mixtures. Sphingomyelin stabilizes the gel phase and thus decreases ceramide miscibility in the presence of cholesterol. Gel/liquid-ordered/liquid-disordered phase coexistence was visualized in quaternary phosphatidylcholine/sphingomyelin/ceramide/cholesterol mixtures as occurrence of dark leaf-like and circular domains within a bright liquid phase. Sphingomyelin initiates specific ceramidesphingomyelin interactions to form a highly ordered gel phase appearing at temperatures higher than pure ceramide gel phase in phosphatidylcholine/ceramide mixtures. Less sphingomyelin is engaged in formation of liquid-ordered phase leading to a shift in its formation to lower temperatures. Sphingomyelinase activity on substrate vesicles destroys micron L o domains but induces the formation of a gel-like phase. The activation of phospholipase A 2 by ceramide on heterogeneous membranes was visualized. Changes in the phase state of the membrane bilayer initiates such morphological processes as membrane fragmentation, budding in and budding out was demonstrated. j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a m e m
Biological activity of ceramides and other sphingolipids
Postepy Dermatologii I Alergologii
Sphingolipids are a large group of lipids which play a key role in the cellular life cycle. In addition to structural functions (they are constituents of cell membranes), they are known to be involved in processes of intercellular recognition and signal transmission. Ceramides, which are sphingolipid metabolites, take part in signal transduction and initiation of a range of processes which affect the cell life. Depending on the external stimulus and cell type, the processes may include inhibition of proliferation, initiation of differentiation or apoptosis. For example, studies have shown that an increased concentration of endogenous ceramides caused by activation of the membrane receptor CD95 activates a number of processes triggering programmed cell death. At the same time, study results have demonstrated that due to their specific structure ceramides are able to interact directly with a number of key enzymes and activate them. What is more, not only endogenous ceramides have the ...
The Physical Properties of Ceramides in Membranes
Annual review of biophysics, 2018
Ceramides are sphingolipids containing a sphingosine or a related base, to which a fatty acid is linked through an amide bond. When incorporated into a lipid bilayer, ceramides exhibit a number of properties not shared by almost any other membrane lipid: Ceramides ( a) are extremely hydrophobic and thus cannot exist in suspension in aqueous media; ( b) increase the molecular order (rigidity) of phospholipids in membranes; ( c) give rise to lateral phase separation and domain formation in phospholipid bilayers; ( d) possess a marked intrinsic negative curvature that facilitates formation of inverted hexagonal phases; ( e) make bilayers and cell membranes permeable to small and large (i.e., protein-size) solutes; and ( f) promote transmembrane (flip-flop) lipid motion. Unfortunately, there is hardly any link between the physical studies reviewed here and the mass of biological and clinical studies on the effects of ceramides in health and disease.
Biochimica Et Biophysica Acta-biomembranes, 2006
Some of the simplest sphingolipids, namely sphingosine, ceramide, some closely related molecules (eicosasphingosine, phytosphingosine), and their phosphorylated compounds (sphingosine-1-phosphate, ceramide-1-phosphate), are potent metabolic regulators. Each of these lipids modifies in marked and specific ways the physical properties of the cell membranes, in what can be the basis for some of their physiological actions. This paper reviews the mechanisms by which these sphingolipid signals, sphingosine and ceramide in particular, are able to modify the properties of cell membranes.
Ceramide-platform formation and -induced biophysical changes in a fluid phospholipid membrane
Molecular Membrane Biology, 2006
To understand the formation and properties of ceramide-enriched domains in cell membranes, the biophysical properties of the binary system palmitoyloleoylphosphatidylcholine (POPC)/palmitoylceramide were thoroughly characterized. Diverse fluorescent probes and parameters were necessary to unravel the complexity of this apparently simple system. For the first time, a complete phase diagram is reported, characterizing the lamellar phases of these mixtures, and providing a quantitative framework integrating biophysical and biological studies. The diagram suggests that in resting cells no ceramide domains exist, but upon apoptotic stimuli, platforms may form. Moreover, our data show that 2 mol% of Cer strongly affects the POPC fluid matrix, suggesting that a small increase in Cer levels can significantly affect cell membrane properties. In this work, we also show that Cer domains, formed in conditions similar to physiological, are extremely ordered and rigid. The domains composition is estimated from the phase diagram and their large size was concluded from fluorescence resonance energy transfer. Dynamic light scattering and electron microscopy were used to characterize the system morphology, which is highly dependent on ceramide content and includes vesiculation and tubular structure formation.