RT Journal Article
SR Electronic
T1 Mechanistic insights into the activation of lecithin-cholesterol acyltransferase in therapeutic nanodiscs composed of apolipoprotein A-I mimetic peptides and phospholipids
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.09.495129
DO 10.1101/2022.06.09.495129
A1 Laura Giorgi
A1 Akseli Niemelä
A1 Esa-Pekka Kumpula
A1 Ossi Natri
A1 Petteri Parkkila
A1 Juha T. Huiskonen
A1 Artturi Koivuniemi
YR 2022
UL http://biorxiv.org/content/early/2022/06/09/2022.06.09.495129.abstract
AB The mechanistic details behind the activation of lecithin-cholesterol acyltransferase (LCAT) by apolipoprotein A-I (apoA-I) and its mimetic peptides are still enigmatic. Resolving the fundamental principles behind the LCAT activation will facilitate the design of advanced HDL-mimetic therapeutic nanodiscs for LCAT deficiencies and coronary heart disease, and for several targeted drug delivery applications. Here, we have combined coarse-grained molecular dynamics simulations with complementary experiments to gain mechanistic insight into how apoA-I mimetic peptide 22A and its variants attune LCAT activity in peptide-lipid nanodiscs. Results highlight that peptide 22A forms transient antiparallel dimers in the rim of nanodiscs. The dimerization tendency considerably decreases with the removal of C-terminal lysine K22, which has also been shown to reduce the cholesterol esterification activity of LCAT. In addition, our simulations revealed that LCAT prefers to localize to the rim of nanodiscs in a manner that shields the membrane-binding domain (MBD), αA-αA’, and the lid amino acids from the water phase, following the previous experimental evidence. Meanwhile, the location and conformation of LCAT in the rim of nanodisc are spatially more restricted when the active site covering lid of LCAT is in the open form. The average location and spatial dimensions of LCAT in its open form were highly compatible with the electron microscopy images. All peptide 22A variants studied here had a specific interaction site in the open LCAT structure flanked by the lid and MBD domain. The bound peptides showed different tendencies to form antiparallel dimers and, interestingly, the temporal binding site occupancies of the peptide variants affected their in vitro ability to promote LCAT-mediated cholesterol esterification.Competing Interest StatementThe authors have declared no competing interest.