Modulation of Membrane Curvature by Phosphatidic Acid and Lysophosphatidic Acid

Abstract

The local generation of phosphatidic acid plays a key role in the regulation of intracellular membrane transport through mechanisms which are largely unknown. Phosphatidic acid may recruit and activate downstream effectors, or change the biophysical properties of the membrane and directly induce membrane bending and/or destabilization. To evaluate these possibilities, we determined the phase properties of phosphatidic acid and lysophosphatidic acid at physiological conditions of pH and ion concentrations. In single-lipid systems, unsaturated phosphatidic acid behaved as a cylindrical, bilayer-preferring lipid at cytosolic conditions (37°C, pH 7.2, 0.5 mM free Mg 2+ ), but acquired a type-II shape at typical intra-Golgi conditions, a mildly acidic pH and submillimolar free Ca 2+ (pH 6.6±5.9, 0.3 mM Ca 2+ ). Lysophosphatidic acid formed type-I lipid micelles in the absence of divalent cations, but anhydrous cationlysophosphatidic acid bilayer complexes in their presence. These data suggest a similar molecular shape for phosphatidic acid and lysophosphatidic acid at cytosolic conditions; however, experiments in mixed-lipid systems indicate that their shape is not identical. Lysophosphatidic acid stabilized the bilayer phase of unsaturated phosphatidylethanolamine, while the opposite effect was observed in the presence of phosphatidic acid. These results support the hypothesis that a conversion of lysophosphatidic acid into phosphatidic acid by endophilin or BARS (50 kDa brefeldin A ribosylated substrate) may induce negative spontaneous monolayer curvature and regulate endocytic and Golgi membrane fission. Alternative models for the regulation of membrane fission based on the strong dependence of the molecular shape of (lyso)phosphatidic acid on pH and divalent cations are also discussed.

Spontaneous Curvature of Phosphatidic Acid and Lysophosphatidic Acid

“…The aim of the current study was to directly measure the spontaneous curvature (the inverse of the spontaneous radius of curvature) of PA and LPA at a physiological pH and salt concentration. Our study extends previous more qualitative studies on the molecular shape of (L)PA (21)(22)(23)(24), and now allows theoretical models of biomembrane fission to be developed (3,16). We show that, under physiological conditions of pH and ionic strength, PA has a negative spontaneous curvature that is slightly less pronounced than that of dioleoylphosphatidylethanolamine (DOPE), while LPA has a spontaneous curvature that is considerably more positive than that of lysophosphatidylcholine (LPC).…”

ArfGAP1 promotes COPI vesicle formation by facilitating coatomer polymerization

“…58 The high content of unsaturated lipid increases the elasticity of the bilayer 59,60 and, consequently, the membranes are easier to deform. Phosphatidic acid, used in as least two reports 58,61 induces membrane curvature, [62][63][64] which would favor vesicle budding. In other work, vesicles contained a peptide from the cargo protein p23, which does not bind ArfGAP1, 34,36 10% phosphatidylinositol 4,5-bisphosphate, which does not occur in the Golgi apparatus, and 30% phosphatidylserine, for the EM studies.…”

What Makes the Bioactive Lipids Phosphatidic Acid and Lysophosphatidic Acid So Special?

“…This would result in PA with more negative curvature in the Golgi luminal leaflet than in the cytoplasmic leaflet. If PA formed in the cytoplasmic leaflet would be able to translocate (49) to the luminal site, it might facilitate the fission of the budding transport carrier by CtBP3/BARS (11,50,51). Thus, a defined charge of (L)PA at a particular (intra)cellular location, determined largely by the local PC:PE ratio, may be a key element of the action of (L)PA at that specific location, and regulate protein recruitment, activation, etc.…”

“…They are involved in many intracellular processes, and are important intermediates in lipid biosynthesis (1). For example, binding of LPA to its receptors evokes various cellular responses, and the local formation of (L)PA is part of signaling cascades, in particular in the regulation of membrane dynamics such as fusion and fission events, either indirectly through the recruitment of downstream effectors or directly by mediating (local) changes in the biophysical properties of the membrane (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”