Structural aspects and activation mechanism of human secretory group IIA phospholipase
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ORIGINAL ARTICLE
Structural aspects and activation mechanism of human secretory group IIA phospholipase Anna K. Manukyan1 Received: 21 May 2020 / Revised: 12 August 2020 / Accepted: 14 August 2020 / Published online: 27 August 2020 © European Biophysical Societies’ Association 2020
Abstract Phospholipases are important probes for understanding structure–function relationships of membrane proteins. Many neurotoxins have phospholipase activity, and they have been recognized to be potential therapeutic agents for biological warfare. Understanding the modes of action of these enzymes is important for the development of effective therapeutic strategies. Human secretory phospholipases A2 ( sPLA2) interact with cellular membranes and catalyze the hydrolysis of phosphate ester bonds of phospholipids. The activity of these enzymes increases tremendously upon binding to a hydrophobic interface. Using molecular dynamics (MD) simulations in implicit solvent and membrane environments, we investigated alterations in structure and conformation of human sPLA2 upon its interaction with a membrane that may be associated with the activation of the enzyme. In 50 ns MD simulations, starting from six different initial orientations of the protein relative to the membrane surface, the enzyme consistently adopted a membrane-bound configuration in close agreement with the known experimental data. The simulations also reproduced the experimentally determined distribution of hydrophobic and polar side chains on the interfacial binding surface. Differences in the dynamic behavior of the enzyme between the solvent and membrane-bound states were observed. In nonpolar media, the enzyme underwent major conformational rearrangements, which exposed the active site to the membrane. The increased mobility of the surface loop and the β-wing regions is required for the conformational change, which is essentially induced by the movement of N-terminal helix. Several active site residues underwent structural changes that reorganize the binding site for substrate catalysis. Overall, the results provided a valuable insight into the interfacial behavior of sPLA2 enzyme and suggested that membrane binding is essential but insufficient for sPLA2 activation. Keywords Secreted phospholipase · Molecular dynamics simulation · Interfacial activation · Membrane binding · Conformational dynamics
Introduction The process of cellular signaling and membrane trafficking is highly organized, and involves complex arrays of macromolecular interactions (Teruel and Meyer 2000). Peripheral proteins, such as phospholipases A 2 (PLA2), play a crucial role in signal transduction, and have been shown Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00249-020-01458-5) contains supplementary material, which is available to authorized users. * Anna K. Manukyan [email protected] 1
Department of Natural Sciences, CUNY Hostos Community College, 475 Grand Concourse, Bronx, NY 10451, USA
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