Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition

• The first crystal structure of cytosolic phospholipase A2 bound to an inhibitor
• The first crystal structure of GIVD cytosolic phospholipase A2
• An unexpected three-domain architecture consisting of two C2 domains and one catalytic domain
• Unique inhibitor-binding or substrate-binding pocket
• Striking inhibitor-induced conformational changes
• Novel inter-domain interface between the C2 domains and the catalytic domain

Cytosolic phospholipases A2 (cPLA2s) consist of a family of calcium-sensitive enzymes that function to generate lipid second messengers through hydrolysis of membrane-associated glycerophospholipids. The GIVD cPLA2 (cPLA2δ) is a potential drug target for developing a selective therapeutic agent for the treatment of psoriasis. Here, we present two X-ray structures of human cPLA2δ, capturing an apo state, and in complex with a substrate-like inhibitor. Comparison of the apo and inhibitor-bound structures reveals conformational changes in a flexible cap that allows the substrate to access the relatively buried active site, providing new insight into the mechanism for substrate recognition. The cPLA2δ structure reveals an unexpected second C2 domain that was previously unrecognized from sequence alignments, placing cPLA2δ into the class of membrane-associated proteins that contain a tandem pair of C2 domains. Furthermore, our structures elucidate novel inter-domain interactions and define three potential calcium-binding sites that are likely important for regulation and activation of enzymatic activity. These findings provide novel insights into the molecular mechanisms governing cPLA2's function in signal transduction.

Graphical AbstractFigure optionsDownload high-quality image (272 K)Download as PowerPoint slide