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Evolution of Phospholipases A 2 in Catalysis and Allosteric Regulation by Membranes
Author(s) -
Mouchlis Varnavas D,
McCammon J. Andrew,
Dennis Edward A
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.833.3
Subject(s) - phospholipid , membrane , lipid bilayer , chemistry , allosteric regulation , biophysics , intracellular , enzyme , biochemistry , bilayer , phospholipase , biology
Defining the molecular details and consequences of the association of water‐soluble proteins with membranes is fundamental to understanding protein–lipid interactions and membrane functioning.1 Phospholipase A 2 (PLA 2 ) enzymes, which catalyze the hydrolysis of phospholipid substrates that comprise the membrane bilayer, provide the ideal system for studying protein–lipidinteractions.2 Our current study focuses on understanding the catalyticcycle of two different recombinant human intracellular PLA 2 s: the GIVA cPLA 2 and GVIA iPLA 2 , which are responsible forarachidonic acid release for eicosanoid signaling and for membrane phospholipidre modeling, respectively. Molecular dynamics (MD) simulations, guided by hydrogen/deuterium exchange mass spectrometric (DXMS)3 experimental data, were used to show that the channel to the active sites of these PLA 2 s are opened upon all ostericinteraction of the enzyme surface with the membrane to facilitate entry of the substrate phospholipid. This constitutes the first detailed study describing the binding and the interaction mechanism of intracellular PLA 2 s with the membrane bilayer as well as how they bind a single phospholipid molecule in the catalytic site. These enzymes are implicated in many diseases, and understanding their detailed mechanism of action will aid in the discovery of new therapeutics. Support or Funding Information Acknowledgements This work was supportedby NIH Grant GM20501