Phospholipase A2 structure/function, mechanism, and signaling

Abstract

Tremendous advances in understanding the structure and function of the superfamily of phospholipase A2 (PLA2) enzymes has occurred in the twenty-first century. The superfamily includes 15 groups comprising four main types including the secreted sPLA2, cytosolic cPLA2, calcium-independent iPLA2, and platelet activating factor (PAF) acetyl hydrolase/oxidized lipid lipoprotein associated (Lp)PLA2. We review herein our current understanding of the structure and interaction with substrate phospholipids, which resides in membranes for a representative of each of these main types of PLA2. We will also briefly review the development of inhibitors of these enzymes and their roles in lipid signaling.

Fig. 1.

A: The group IA phospholipase A₂ (PLA₂) with phospholipid substrate modeled in the active site. The active site residues His-48 and Asp-93 and the bound Ca²⁺ is shown in purple. Ca²⁺ is bound by Asp-49 as well as the carbonyl oxygens of Tyr-28, Gly-30, and Gly-32. Aromatic residues are shown in white. Adapted from Dennis (9). B: Model of the lipid surface binding of the group IA PLA₂ is shown with residues on the interfacial binding surface Tyr-3, Trp-19, Trp 61, and Phe 64 shown in stick form. Adapted from Burke et al. (20).

Fig. 2.

A: Group IVA PLA₂ crystal structure as determined by Dessen et al. (33). The C2 domain is shown in orange, with two bound Ca²⁺ ions shown in purple. The catalytic domain is shown on the right with the cap region colored yellow, and the lid region 415–432 colored magenta. The active site residues Ser-228, Asp-549, and Arg-200 are shown in stick form colored red. The PIP₂ binding site is shown in dark blue, and the C1P binding site is shown in cyan. B: Model of the lipid-binding surface of the group IVA (GIVA) PLA₂ with residues colored based on interaction with lipid membrane. Adapted from Burke et al (35).