title: Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition.
abstract: 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.
authors.affiliation: Department of Structural Biology, Takeda California, San Diego, CA 92121, USA. Electronic address: wanghui.takeda@gmail.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Structural Biology, Takeda California, San Diego, CA 92121, USA. Electronic address: michaelgklein@gmail.com.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Klein
authors.affiliation: Department of Structural Biology, Takeda California, San Diego, CA 92121, USA.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Snell
authors.affiliation: Department of Structural Biology, Takeda California, San Diego, CA 92121, USA.
authors.forename: Weston
authors.initials: W
authors.lastname: Lane
authors.affiliation: Department of Structural Biology, Takeda California, San Diego, CA 92121, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zou
authors.affiliation: Department of Structural Biology, Takeda California, San Diego, CA 92121, USA.
authors.forename: Irena
authors.initials: I
authors.lastname: Levin
authors.affiliation: Department of Structural Biology, Takeda California, San Diego, CA 92121, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Structural Biology, Takeda California, San Diego, CA 92121, USA.
authors.forename: Bi-Ching
authors.initials: BC
authors.lastname: Sang
mesh_terms: D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding / Q000235:genetics*; D000072417:Protein Domains; D015290:Second Messenger Systems / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013379:Substrate Specificity / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D054513:Group IV Phospholipases A2; D002118:Calcium
keywords: C2 domain; cPLA(2); calcium binding; inhibitor; α/β hydrolase