title: Lipoprotein-associated phospholipase A(2) interacts with phospholipid vesicles via a surface-disposed hydrophobic α-helix.
abstract: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) plays important roles in both the inhibition and promotion of inflammation in human disease. It catalyzes the hydrolytic inactivation of plasma platelet activating factor (PAF) and is also known as PAF acetylhydrolase. High levels of PAF are implicated in a variety of inflammatory diseases such as asthma, necrotizing enterocolitis, and sepsis. Lp-PLA(2) also associates with lipoproteins in human plasma where it hydrolyzes oxidized phospholipids to produce pro-inflammatory lipid mediators that can promote inflammation and the development of atherosclerosis. Lp-PLA(2) plasma levels have recently been identified as a biomarker of vascular inflammation, atherosclerotic vulnerability, and future cardiovascular events. The enzyme is thus a prominent target for the development of inflammation and atherosclerosis-modulating therapeutics. While the crystallographically determined structure of the enzyme is known, the enzyme's mechanism of interaction with PAF and the function-modulating lipids in lipoproteins is unknown. We have employed peptide amide hydrogen-deuterium exchange mass spectrometry (DXMS) to characterize the association of Lp-PLA(2) with dimyristoylphosphatidylcholine (DMPC) vesicles and found that specific residues 113-120 in one of the enzyme's surface-disposed hydrophobic α-helices likely mediate liposome binding.
authors.affiliation: Department of Chemistry and Biochemistry and Pharmacology, University of California, La Jolla, CA 92093-0601, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.forename: Yuan-Hao
authors.initials: YH
authors.lastname: Hsu
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.forename: Virgil L
authors.initials: VL
authors.lastname: Woods
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000737:chemistry* / Q000378:metabolism; D002384:Catalysis; D041961:Deuterium Exchange Measurement; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D013499:Surface Properties
chemical_list: D010743:Phospholipids; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase