ApoE and ApoE Nascent-Like HDL Particles at Model Cellular Membranes: Effect of Protein Isoform and Membrane Composition

Abstract

Apolipoprotein E (ApoE), an important mediator of lipid transportation in plasma and the nervous system, plays a large role in diseases such as atherosclerosis and Alzheimer's. The major allele variants ApoE3 and ApoE4 differ only by one amino acid. However, this difference has major consequences for the physiological behaviour of each variant. In this paper, we follow (i) the initial interaction of lipid-free ApoE variants with model membranes as a function of lipid saturation, (ii) the formation of reconstituted High-Density Lipoprotein-like particles (rHDL) and their structural characterisation, and (iii) the rHDL ability to exchange lipids with model membranes made of saturated lipids in the presence and absence of cholesterol [1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) with and without 20 mol% cholesterol]. Our neutron reflection results demonstrate that the protein variants interact differently with the model membranes, adopting different protein conformations. Moreover, the ApoE3 structure at the model membrane is sensitive to the level of lipid unsaturation. Small-angle neutron scattering shows that the ApoE containing lipid particles form elliptical disc-like structures, similar in shape but larger than nascent or discoidal HDL based on Apolipoprotein A1 (ApoA1). Neutron reflection shows that ApoE-rHDL do not remove cholesterol but rather exchange saturated lipids, as occurs in the brain. In contrast, ApoA1-containing particles remove and exchange lipids to a greater extent as occurs elsewhere in the body.

SARS-CoV-2 spike protein removes lipids from model membranes and interferes with the capacity of high density lipoprotein to exchange lipids

“…It was noted previously that more lipid molecules are removed than deposited by HDL [14,16,17]. The results here could be a peculiarity of this pooled HDL sample, which may contain altered proportions of apolipoprotein variants having for example altered affinity for lipid exchange [34]. Membrane co-incubation of both HDL and S protein maintains this trend (Fig.…”

“…Thus, it seems likely that cholesterol is the main component removed by S protein from the membrane. Additional NR experiments could clarify whether or not both phospholipids and cholesterol are removed equally: for example, by using membranes containing different combinations of hydrogenated or deuterated membrane components, the specific removal of either cholesterol or phospholipids could be determined as done previously for ApoE-based reconstituted HDL [34]. We attempted to carry out ATR-FTIR experiments with hDMPC and dcholesterol model membranes, but the CD 2 bands were, in this case, too weak to draw any conclusions from the data (probably due to the low cholesterol molar content used in these experiments).…”

Expanding the Toolbox for Bicelle-Forming Surfactant–Lipid Mixtures

“…The bilayer head groups (face) and core thickness values were comparable for bicelles composed of DHPC and CHAPS, and ranged around 23–25 Å for the tail region and 9–12 Å for the head groups, except for DMPC–CHAPS at q = 0.5. The headgroup and core thickness values are consistent with those of a DMPC lipid bilayer core in the fluid phase [ 20 , 21 , 22 ]. The rim thickness stabilized above q = 1.5 at approximately 8 and 4 Å for CHAPS and DHPC, respectively.…”

High-Density Lipoprotein function is modulated by the SARS-CoV-2 spike protein in a lipid-type dependent manner

“…For example, the cholesterol content in membranes regulates the membrane fluidity and membrane packing, depending on the acyl chain composition of the lipids present [43] . A change in the HDL lipid composition might translate to a shift in the HDL-apolipoprotein composition, which affects HDL functionality [44] .…”