Interaction of lecithin-cholesterol acyltransferase with lipid surfaces and apolipoprotein A-I derived peptides

Publication year: 2018
Authors: Casteleijn M. G., Parkkila P., Viitala T., Koivuniemi A.
Affiliations:

Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Finland

Published in: Journal of Lipid Research, 2018
doi: 10.1194/jlr.M082685

Lecithin-cholesterol acyltransferase (LCAT) is an enzyme responsible for the formation of cholesteryl esters from unesterified cholesterol (UE) and phospholipid (PL) molecules in high-density lipoprotein (HDL) particles. However, it is poorly understood how LCAT interacts with lipoproteins and how apolipoprotein A-I (apoA-I) activates it. Here we have studied the interactions between LCAT and lipids through molecular simulations. In addition, we studied the binding of LCAT to apoA-I derived peptides, and their effect on LCAT lipid association utilizing experiments. Results show that LCAT anchors itself to lipoprotein surfaces by utilizing non-polar amino acids located in the membrane-binding domain and the active site tunnel opening. Meanwhile, the membrane anchoring hydrophobic amino acids attract cholesterol molecules next to them. The results also highlight the role of the lid-loop in the lipid binding and conformation of LCAT with respect to the lipid surface. The apoA-I derived peptides from the LCAT activating region bind to LCAT and promote its lipid surface interactions, although some of these peptides do not bind lipids individually. The transfer free-energy of PL to the active site is consistent with the activation energy of LCAT. Furthermore, the entry of UE molecules into the active site becomes highly favorable by the acylation of SER181.


MP-SPR keywords: affinity, effect of peptides on the binding of LCAT, enzyme – peptide interaction, lecithin cholesterol acyl transferase (LCAT) enzyme binding on lipid bilayers, simulations, streptavidin - biotin interaction