Differential Membrane Packing of Stereoisomers of Bis(monoacylglycero)phosphate

Abstract

Bis(monoacylglycero)phosphate (BMP) reveals an unusual sn-1,sn-1′ stereoconfiguration of glycerophosphate. We synthesized sn- (3-myristoyl-2-hydroxy)glycerol-1-phospho-sn-1′-(3′-myristoyl-2′-hydroxy)glycerol (1,1′-DMBMP) and characterized the thermotropic phase behavior and membrane structure, in comparison with those of the corresponding sn-3:sn-1′ stereoisomer (3,1′-DMBMP), by means of differential scanning calorimetry (DSC), small-and wide-angle X-ray scattering (SAXS and WAXS, respectively), pressure-area (π-A) isotherms, epifluorescence microscopy of monolayers, and molecular dynamics (MD) simulations. In DSC, these lipids exhibited weakly energetic broad peaks with an onset temperature of 9°C for 1,1′-DMBMP and 18°C for 3,1′-DMBMP. In addition, a highly cooperative, strongly energetic transition peak was observed at ∼40°C for 1,1′-DMBMP and ∼42°C for 3,1′-DMBMP. These results are supported by the observation that 1,1′-DMBMP exhibited a larger phase transition pressure (π c ) than 3,1′-DMBMP. Small-and wide-angle X-ray scattering measurements identified these small and large energetic transitions as a quasi-crystalline (L c1 )-quasi-crystalline with different tilt angle (L c2 ) phase transition and an L c2 -L R main phase transition, respectively. X-ray measurements also revealed that these DMBMPs undergo an unbinding at the main phase transition temperature. The MD simulations estimated stronger hydrogen bonding formation in the 3,1′-DMBMP membrane than in 1,1′-DMBMP, supporting the experimental data.Bis(monoacylglycero)phosphate, also known as lysobisphosphatidic acid (LBPA), was first described in pig and rabbit pulmonary alveolar macrophages by Body and Gray (1). BMPs comprise less than 1% of the total phospholipids in most mammalian cells (2, 3). However, the content is increased to 15% in late endosomes (4). In the specific internal membrane domains of this organelle, this lipid comprises more than 70% of the total phospholipids (5).Because of the high level of accumulation in late endosomes, BMP is assumed to be important for the structural and functional integrity of the organelle. Indeed, a series of experiments has demonstrated that agents that perturb BMP induce alterations in the sorting and trafficking of proteins and/or the receptor in late endosomes accompanied by structural changes of the late edonsome organelle (4, 6) along with abnormal accumulation of cholesterol (7). Moreover, BMP is found to be essential for the activator-stimulated hydrolysis of ganglioside G M1 (8) and G M2 (9) and for the hydrolysis of ceramide by acid ceramidase (10).BMP has unique structural characteristics with various fatty acid compositions depending on the source. Whereas all other mammalian phospholipids display a sn-3-glycerophosphate stereoconfiguration, BMP possesses an sn-1:sn-1′ structure and one acyl group attached to each of the glycerol moieties (11-13). An sn-3:sn-1′ isomer has also been reported for BMP in BHK cells (14). However, the sn-3:sn-1′ isomer in mammalian cells is postulated to be...

N-Terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes

“…As observed in Fig. 4F, 14BMP displays two endothermic peaks on heating, a small transition at about 19°C from a quasicrystalline phase L c1 to a quasi-crystalline phase with different tilt angle L c2 and a main transition at about 41°C from a quasi-crystalline phase L c2 to the liquid phase L α [53]. The incorporation of NS4B AH2 into 14BMP membranes at a lipid/peptide ratio of 15:1 did not alter the thermotropic behavior of the phospholipid, since no significant effect was observed on the two transitions of 14BMP (Fig.…”

Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid

“…1,2,3-Tridocosahexaenoyl-sn-glycerol (tri22:6-TG) was from Polariz (Pleuven, France). sn-(3-Pentadecanoyl-2-hydroxy)-glycerol-1-phospho-sn-1′-(3′-pentadecanoyl-2′-hydroxy)-glycerol (15:0/15:0-BMP) and sn-(3-docosahexaenoyl-2-hydroxy)-glycerol-1-phosphosn-1′-(3′-docosahexaenoyl-2′-hydroxy)-glycerol (22:6/22:6-BMP) were chemically synthesized by our chemist colleagues according to the method previously described (30). [1a,2a(n)- …”

Bis(monoacylglycero)phosphate: a secondary storage lipid in the gangliosidoses

“…Kobayashi and colleagues showed that BMP plays a role in the formation, structure, and traffi cking of endosomal/lysosomal compartments in cells under normal conditions ( 3,57,59 ). Late endosomes/lysosomes form multivesicular bodies under normal conditions, but form multilamellar vesicles in pathological cases such as the gangliosidoses ( 60,61 ). Both gangliosides and BMP are thought necessary for the formation of these aberrant lamellar bodies.…”