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

by Nicolas Henry, Eva-Maria Krammer, Florian Stengel, Quentin Adams, Fran çois Van Liefferinge, Ellen Hubin, Rui Chaves, Rouslan Efremov, Ruedi Aebersold, Guy Vandenbussche, Martine Prévost, Vincent Raussens, Stéphanie Deroo Apolipoprotein E (apoE) is a forefront actor in the transport of lipids and the maintenance of cholesterol homeostasis, and is also strongly implicated in Alzheimer’s disease. Upon lipid-binding apoE adopts a conformational state that mediates the receptor-induced internalization of lipoproteins . Due to its inherent structural dynamics and the presence of lipids, the structure of the biologically active apoE remains so far poorly described. To address this issue, we developed an innovative hybrid method combining experimental data with molecular modeling and dynamics to generate comprehens ive models of the lipidated apoE4 isoform. Chemical cross-linking combined with mass spectrometry provided distance restraints, characterizing the three-dimensional organization of apoE4 molecules at the surface of lipidic nanoparticles. The ensemble of spatial restraints was then rationalized in an original molecular modeling approach to generate monomeric models of apoE4 that advocated the existence of two alternative conformations. These two models point towards an activation mechanism of apoE4 relying on a regulation of the accessibility of its receptor binding region. Further, molecular d ynamics simulations of the dimerized and lipidated apoE4 monomeric con...
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research