Investigating the association and interactions of phospholipases A2 (PLA2) with lipid bilayers is fundamental to understanding their catalytic cycle. The PLA2 superfamily consists of 16 groups and many subgroups and constitutes a diverse set of enzymes that have a common catalytic activity. This study focuses on four human enzymes: the cytosolic (cPLA2), calcium-independent (iPLA2), secreted (sPLA2) and lipoprotein-associated (Lp-PLA2). cPLA2 is the main arachidonic acid provider for the eicosanoid pathway, while iPLA2 is involved in membrane phospholipid remodeling. sPLA2 is involved in atherosclerosis, and Lp-PLA2 is implicated in cardiovascular diseases through its association with LDL and HDL in human plasma. Hydrogen/deuterium exchange mass spectrometry was used to experimentally identify distinct PLA2 peptide regions that interact with phospholipid vesicles. Molecular dynamics simulations on enzyme-membrane interactions models showed that the interfacial surface affects the association of each enzyme with membrane surface. Membrane phospholipids bind to allosteric sites located on the interfacial surface of PLA2s shifting their conformation from the “closed” to the “open” state. This process facilitates extraction and binding of a phospholipid molecule in the active site where the hydrolysis occurs. This constitutes the first detailed study describing the binding and interaction mechanism of PLA2s with the membrane bilayer indicating that enzyme substrate specificity depends on membrane association. These enzymes are implicated in chronic inflammatory diseases and understanding their association with membranes, mechanism of action and interactions at the molecular level, will allow us to identify potent and selective inhibitors that can be further developed as anti-inflammatory agents.

Surface dilution kinetics: The association of phospholipase A<sub>2</sub> with lipid-bilayers

256th National Meeting (2018)

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Surface dilution kinetics: The association of phospholipase A2 with lipid-bilayers

Surface dilution kinetics: The association of phospholipase A₂ with lipid-bilayers