Phosphatidic acid is one of the simplest and smallest classes of glycerophospholipids that plays an important role in mediating a wide range of cellular and physiological processes in eukaryotes from microbes to mammals and higher plants. As with all other phospholipids, phosphatidic acid composes part of the membrane lipid bilayer and contributes to the membrane’s physical properties. At physiological pH, phosphatidic acid has a net charge of about 1.5 and so it is a strong anion that contributes negative charge density to the membrane.
Structure and shape of phosphatidic acid
Phosphatidic acid is an amphipathic phospholipid consisting of a polar head group and two hydrophobic acyl tails. As shown in Figure 1A, the phosphate in the polar head group of the phosphatidic acid molecule contains two hydroxyl groups and an ester bond. At physiological pH, at least one of the two phosphatidic acid hydroxyl groups is usually deprotonated. Therefore, the phosphatidic acid is negatively charged. Phosphatidic acid has a unique shape. It has a wider tail than its head group and can be modeled as a cone. The monolayer consisting of phosphatidic acid molecules tends to bulge spontaneously towards the hydrocarbon tails and to form inverted hexagonal phase (HII), with an aqueous core surrounded by the hydrophilic headgroups, and hydrophobic tails aggregating around the perimeter. This cone shaped phosphatidic acid has a negative spontaneous curvature.
Figure 1. (A) General phosphatidic acid structure; (B) Phosphatidic acids in a conical shape. They promote the formation of inverted hexagonal phase or inverted micelles .
The role of phosphatidic acid in membrane fusion and membrane fission
Phosphatidic acid is a unique lipid molecule that plays an important role in membrane fusion and membrane fission. It is involved in numerous membrane fusion/fission events such as Golgi membrane fission, fission during endocytic transport, osteoclast fusion, vesicle-vesicle fusion, myoblast fusion, and membrane fusion during sporulation, and vacuole fission and fusion. Typically, phosphatidic acid affects membrane fusion and fission through four mechanisms described below.
(i) The increased local concentration of phosphatidic acid (in yellow) leads to the accumulation of negative charges and membrane packing defects that allow the recruitment of membrane fission/fusion-inducing proteins containing positively charged residues (as shown by green stars). These inducible proteins are used to mediate membrane fusion and membrane fission reactions (as shown in Figure 2A).
(ii) The local accumulation of phosphatidic acid (in yellow) produces membrane rearrangement by promoting the negative curvature of the membrane (as shown in Figure 2B).
(iii) Phosphatidic acid (in yellow) stimulates enzyme activity and the products of these enzymes are involved in membrane rearrangement (as shown in Figure 2C).
(iv) Phosphatidic acid is a substrate for enzymes producing other lipids. It can be converted to diacylglycerol (DAG) or lysophosphatidic acid (LPA) which can affect cell membrane rearrangement (as shown in Figure 2D).
Figure 2. Schematic representation of membrane rearrangements influenced by phosphatidic acid .
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- Valente, C.; et al. Phosphatidic acid in membrane rearrangements. FEBS Letters. 2019, 593: 2428-2451.
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