A novel dimeric active site and regulation mechanism revealed by the crystal structure of iPLA2β

Abstract

Calcium-independent phospholipase A2{beta} (iPLA2{beta}) regulates several physiological processes including inflammation, calcium homeostasis and apoptosis. It is linked genetically to neurodegenerative disorders including Parkinsons disease. Despite its known enzymatic activity, the mechanisms underlying pathologic phenotypes remain unknown. Here, we present the first crystal structure of iPLA2{beta} that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. The ankyrin repeat domains wrap around the catalytic domains in an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. A single calmodulin binds and allosterically inhibits both catalytic domains. These unique structural features identify the molecular interactions that can regulate iPLA2{beta} activity and its cellular localization, which can be targeted to identify novel inhibitors for therapeutic purposes. The structure provides a well-defined framework to investigate the role of neurodegenerative mutations and the function of iPLA2{beta} in the brain.