title: Domain-induced activation of human phospholipase A2 type IIA: local versus global lipid composition.
abstract: Secretory human phospholipase A2 type IIA (PLA2-IIA) catalyzes the hydrolysis of the sn-2 ester bond in glycerolipids to produce fatty acids and lysolipids. The enzyme is coupled to the inflammatory response, and its specificity toward anionic membrane interfaces suggests a role as a bactericidal agent. PLA2-IIA may also target perturbed native cell membranes that expose anionic lipids to the extracellular face. However, anionic lipid contents in native cells appear lower than the threshold levels necessary for activation. By using phosphatidylcholine/phosphatidylglycerol model systems, we show that local enrichment of anionic lipids into fluid domains triggers PLA2-IIA activity. In addition, the compositional range of enzyme activity is shown to be related to the underlying lipid phase diagram. A comparison is done between PLA2-IIA and snake venom PLA2, which in contrast to PLA2-IIA hydrolyzes both anionic and zwitterionic membranes. In general, this work shows that PLA2-IIA activation can be accomplished through local enrichment of anionic lipids into domains, indicating a mechanism for PLA2-IIA to target perturbed native membranes with low global anionic lipid contents. The results also show that the underlying lipid phase diagram, which determines the lipid composition at a local level, can be used to predict PLA2-IIA activity.
authors.affiliation: Department of Physics, Universidad de los Andes, Bogotá, Colombia. cleidy@uniandes.edu.co
authors.forename: Chad
authors.initials: C
authors.lastname: Leidy
authors.forename: Lars
authors.initials: L
authors.lastname: Linderoth
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andresen
authors.forename: Ole G
authors.initials: OG
authors.lastname: Mouritsen
authors.forename: Kent
authors.initials: K
authors.lastname: Jørgensen
authors.forename: Günther H
authors.initials: GH
authors.lastname: Peters
mesh_terms: D000818:Animals; D002152:Calorimetry, Differential Scanning; D005452:Fluoresceins; D054501:Group II Phospholipases A2; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008055:Lipids / Q000737:chemistry*; D021962:Membrane Microdomains / Q000737:chemistry* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000737:chemistry / Q000378:metabolism; D010741:Phospholipases A / Q000737:chemistry / Q000378:metabolism*; D054467:Phospholipases A2; D017434:Protein Structure, Tertiary; D012910:Snake Venoms / Q000201:enzymology; D012911:Snakes / Q000502:physiology
chemical_list: D005452:Fluoresceins; D008055:Lipids; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D012910:Snake Venoms; C002773:dimyristoylphosphatidylglycerol; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; C007740:fluorexon