Antibody-independent activation of C1, the first component of complement, by cardiolipin.
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Lipid vesicles containing phospholipids known to be present in substantial amounts in mitochondrial membranes were tested for their capacity to activate C1. Among them, only cardiolipin (CL) was highly efficient in C1 activation; no such effect was observed with phosphatidylcholine, phosphatidylethanolamine, or phosphatidylinositol. CL was shown to bind specifically C1q, because only unlabeled C1q competed with 125I-C1q for binding to CL. The requirement for C1q was confirmed by the finding that only fully reconstituted macromolecular C1, containing C1q, was activated by CL. The specificity of CL-induced activation of C1 was also demonstrated by introducing adriamycin, an agent known to interact with CL. Whereas adriamycin did not decrease C1 activation induced by immune complexes, it abrogated C1 activation by CL. The latter was shown to be a strong nonimmune activator of C1, because C1-INH did not inhibit CL-induced activation. When the concentration of CL in vesicles was decreased in the presence of phosphatidylcholine, C1 activation was detected only above a critical level of 35 mol% CL, compatible with a minimal density or clustering of CL molecules in the plane of the membrane. Moreover, C1 activation by CL was modulated by the addition of cholesterol. The threshold of CL required for C1 activation was lowered by the incorporation of more than 35 mol% cholesterol into the vesicles. These results show that CL incorporated into liposomes can be a potent nonimmune activator of C1. The negatively charged phosphate groups in CL are likely candidates for Clq-binding.Keywords:
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Membrane proteins interact with phospholipids either via an annular layer surrounding the transmembrane segments or by specific lipid-protein interactions. Although specifically bound phospholipids are observed in many crystal structures of membrane proteins, their roles are not well understood. Na,K-ATPase is highly dependent on acid phospholipids, especially phosphatidylserine, and previous work on purified detergent-soluble recombinant Na,K-ATPase showed that phosphatidylserine stabilizes and specifically interacts with the protein. Most recently the phosphatidylserine binding site has been located between transmembrane segments of αTM8-10 and the FXYD protein. This paper describes stimulation of Na,K-ATPase activity of the purified human α1β1 or α1β1FXYD1 complexes by neutral phospholipids, phosphatidylcholine, or phosphatidylethanolamine. In the presence of phosphatidylserine, soy phosphatidylcholine increases the Na,K-ATPase turnover rate from 5483 ± 144 to 7552 ± 105 (p < 0.0001). Analysis of α1β1FXYD1 complexes prepared with native or synthetic phospholipids shows that the stimulatory effect is structurally selective for neutral phospholipids with polyunsaturated fatty acyl chains, especially dilinoleoyl phosphatidylcholine or phosphatidylethanolamine. By contrast to phosphatidylserine, phosphatidylcholine or phosphatidylethanolamine destabilizes the Na,K-ATPase. Structural selectivity for stimulation of Na,K-ATPase activity and destabilization by neutral phospholipids distinguish these effects from the stabilizing effects of phosphatidylserine and imply that the phospholipids bind at distinct sites. A re-examination of electron densities of shark Na,K-ATPase is consistent with two bound phospholipids located between transmembrane segments αTM8-10 and TMFXYD (site A) and between TM2, -4, -6, -and 9 (site B). Comparison of the phospholipid binding pockets in E2 and E1 conformations suggests a possible mechanism of stimulation of Na,K-ATPase activity by the neutral phospholipid.
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Phosphatidylethanolamine
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The membranes from normal and Plasmodium knowlesi -infected rhesus monkey erythrocytes (90 to 95 percent infected with early ring stage) were analyzed for transbilayer distribution of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS), by means of chemical and enzymatic probes. The external monolayer of the normal red cell membrane contained at least 68 to 72 percent of the total phosphatidylcholine and 15 to 20 percent of the total phosphatidylethanolamine. In the infected cell, the transmembrane phosphatidylcholine distribution appeared to be reversed, with only 20 to 30 percent of it being externally localized, whereas roughly equal amounts of phosphatidylethanolamine were present in the outer and inner surfaces. However, total phosphatidylserine in both the infected and normal red cells was exclusively internal. Unlike that in the normal intact cell, external phosphatidylethanolamine in the parasitized cell was readily accessible to phospholipase A 2 . These results indicate that significant changes in molecular architecture of the host cell membrane are the result of parasitization.
Phosphatidylethanolamine
Cell membrane
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We enriched liver microsomes in lipid classes and molecular species disrupting membranes with octyl glucoside and reassembling them by detergent removal. Phosphatidylethanolamine incorporated into membranes better than phosphatidylserine or phosphatidylcholine. In addition, the degree of incorporation depended on the unsaturation of fatty acyl-chains. The enrichment of the membranes with phosphatidylserine or phosphatidylcholine inhibited serine base-exchange, whereas the addition of phosphatidylethanolamine usually stimulated it. The effect of exogenous lipids also depended on molecular species; egg yolk phosphatidylcholine and dipalmitoyl phosphatidylcholine inhibited base-exchange whereas the effect of palmitoyl-oleoyl phosphatidylcholine depended on the incorporated amount. The degree of unsaturation also modulated the effect of phosphatidylethanolamine.
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Rat brain slices have been incubated in the presence of water-soluble synthetic peptide fragments corresponding to residues 1-9 and 1-15 of the N-terminus of immunophilin and the effects on the phospholipid composition examined. During a 2 h incubation in the presence of 1 nM, 0-1 mu M and 10 mu M concentrations of the peptides there were significant and dose-dependent decreases in the amounts of phosphatidylcholine and phosphatidylethanolamine and increases in the amounts of phosphatidylserine and, to a lesser extent, phosphatidylinositol, cardiolipin and lysophosphatidylcholine. The overall decrease in the neutral phospholipids and increase in the acidic phospholipids tended to counteract any change in the phospholipid composition of the tissue. The results are discussed in terms of the possible effects of immunophilin on modulating phospholipid turnover in brain cell membranes.
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