Lipidated apolipoprotein E4 structure and its receptor binding mechanism determined by a combined cross-linking coupled to mass spectrometry and molecular dynamics approach

摘要

Author summary Among the proteins involved in the transport of lipids and their distribution to the cells, apolipoprotein E (apoE) mediates the internalization of cholesterol rich lipoproteins by acting as a ligand for cell-surface receptors. In the central nervous system, while apoE is the major cholesterol transport protein, a dysfunction of apoE in the transport and metabolism of lipids is associated with Alzheimer’s disease. A molecular understanding of the mechanisms underlying the receptor binding abilities of apoE is crucial to address its biological functions, but is so far hindered by the dynamic and complex nature of these assemblies. We have designed an original hybrid approach combining experimental data and bioinformatics tools to generate high resolution models of lipidated apoE. Based on these models, we can propose how apoE adapts its conformation at the surface of lipid nanoparticles. Further, we propose a novel mechanism of regulation of the activation and receptor recognition of apoE that could prove valuable to interpret its role in Alzheimer and apoE-related cardiovascular diseases.