ApoE and ApoE Nascent-Like HDL Particles at Model Cellular Membranes: Effect of Protein Isoform and Membrane Composition
Research output: Contribution to journal › Journal article › Research › peer-review
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.
| Original language | English |
|---|---|
| Article number | 630152 |
| Journal | Frontiers in Chemistry |
| Volume | 9 |
| ISSN | 2296-2646 |
| DOIs | |
| Publication status | Published - 2021 |
| Externally published | Yes |
Bibliographical note
Funding Information:
We thank the ILL neutron facility for granted beamtimes with DOIs: 10.5291/ILL-DATA.9-13-807 (FIGARO, June, September 2019), 10.5291/ILL-DATA.9-13-894 (FIGARO, February 2020) and 10.5291/ILL-DATA.8-03-979 (D11, September 2020) and the Partnership for Soft Condensed Matter at the ILL for the use of sample preparation facilities. This work benefited from the use of the SasView application, originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union’s Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement No 654000. This work used the EM facilities at the Grenoble Instruct-ERIC Center (ISBG; UMS 3518 CNRS CEA-UGA-EMBL) with support from the French Infrastructure for Integrated Structural Biology (FRISBI; ANR-10-INSB-05-02) and GRAL, a project of the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003) within the Grenoble Partnership for Structural Biology. The IBS Electron Microscope facility is supported by the Auvergne Rhône-Alpes Region, the Fonds Feder, the Fondation pour la Recherche Médicale and GIS-IBiS.
Funding Information:
We thank the ILL neutron facility for granted beamtimes with DOIs: 10.5291/ILL-DATA.9-13-807 (FIGARO, June, September 2019), 10.5291/ILL-DATA.9-13-894 (FIGARO, February 2020) and 10.5291/ILL-DATA.8-03-979 (D11, September 2020) and the Partnership for Soft Condensed Matter at the ILL for the use of sample preparation facilities. This work benefited from the use of the SasView application, originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union's Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement No 654000. This work used the EM facilities at the Grenoble Instruct-ERIC Center (ISBG; UMS 3518 CNRS CEA-UGA-EMBL) with support from the French Infrastructure for Integrated Structural Biology (FRISBI; ANR-10-INSB-05-02) and GRAL, a project of the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003) within the Grenoble Partnership for Structural Biology. The IBS Electron Microscope facility is supported by the Auvergne Rh?ne-Alpes Region, the Fonds Feder, the Fondation pour la Recherche M?dicale and GIS-IBiS. Funding. MC thanks the Swedish Research Council, Grant Number 2014-2981. VF thanks the EPSRC for grants GR/R99393/01 and EP/C015452/1 which funded the creation of the Deuteration Laboratory in ILL's Life Science Group. The National Deuteration Facility in Australia is partly funded by The National Collaborative Research Infrastructure Strategy (NCRIS) an Australian Government initiative. This work was also partly funded by a PhD studentship at the ILL.
Funding Information:
MC thanks the Swedish Research Council, Grant Number 2014-2981. VF thanks the EPSRC for grants GR/R99393/01 and EP/C015452/1 which funded the creation of the Deuteration Laboratory in ILL’s Life Science Group. The National Deuteration Facility in Australia is partly funded by The National Collaborative Research Infrastructure Strategy (NCRIS) an Australian Government initiative. This work was also partly funded by a PhD studentship at the ILL.
Publisher Copyright:
© Copyright © 2021 Waldie, Sebastiani, Moulin, Del Giudice, Paracini, Roosen-Runge, Gerelli, Prevost, Voss, Darwish, Yepuri, Pichler, Maric, Forsyth, Haertlein and Cárdenas.
- ApoE isoforms, lipid exchange, model membranes, neutron reflection, reconstituted HDL, small-angle neutron scattering
Research areas
ID: 348241429