Mechanistic Insights into the Activation of Lecithin-Cholesterol Acyltransferase in Therapeutic Nanodiscs Composed of Apolipoprotein A-I Mimetic Peptides and Phospholipids
Artikel i vetenskaplig tidskrift, 2022

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 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-Imimetic peptide 22A and its variants tune LCAT activity in peptide-lipid nanodiscs. Our 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 previous experimental evidence. Meanwhile, the location and conformation of LCAT in the rim of nanodiscs are spatially more restricted when the active site covering the 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.

acyltransferase

electron microscopy imaging

apolipoprotein mimetics

reverse cholesterol transport

high-density lipoprotein (HDL)

molecular dynamics simulation

Författare

Laura Giorgi

Helsingin Yliopisto

Akseli Niemelä

Helsingin Yliopisto

Esa Pekka Kumpula

Institute of Biotechnology

Ossi Natri

Helsingin Yliopisto

Petteri Parkkila

Helsingin Yliopisto

Chalmers, Fysik, Nano- och biofysik

Juha T. Huiskonen

Institute of Biotechnology

Artturi Koivuniemi

Helsingin Yliopisto

Molecular Pharmaceutics

1543-8384 (ISSN) 1543-8392 (eISSN)

Vol. 19 11 4135-4148

Ämneskategorier

Biokemi och molekylärbiologi

Biofysik

Strukturbiologi

DOI

10.1021/acs.molpharmaceut.2c00540

PubMed

36111986

Mer information

Senast uppdaterat

2024-03-07