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Biophys. J. BioFAST: First Published February 3, 2006. doi:10.1529/biophysj.105.070987
© 2006 by the Biophysical Society.

A more recent version of this article appeared on May 1, 2006.
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MEMBRANES

Domain-Induced Activation of Human Phospholipase A2 type IIA: Local versus Global Lipid Composition

Chad Leidy 1*, Lars Linderoth 2, Thomas L. Andresen 3, Ole G. Mouritsen 4, Kent Jørgensen 5 and Günther H. Peters 6

1 Department of Physics, Universidad de los Andes, Bogota, Colombia
2 Department of Chemistry, Technical University of Denmark
3 Liplasome Pharma A/S, Technical University of Denmark
4 MEMPHYS Center for Biomembrane Physics, Department of Physics, University of Southern Denmark
5 Liplasome Pharma A/S,Technical University of Denmark
6 MEMPHYS Center for Biomembrane Physics, Department of Chemistry, Technical University of Denmark

* To whom correspondence should be addressed. E-mail: cleidy{at}uniandes.edu.co.

Submitted on July 25, 2005
Revised on September 1, 2005
Accepted on 22 December 2005


  Abstract
Secretory human 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 towards 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 trigger 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.

Key Words: anionic lipid, inflammation, lipid domain, lipid phase diagram, lipid phase separation, phospholipase A2




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Copyright © 2006 by the Biophysical Society.