TY - JOUR
T1 - Lipidated apolipoprotein E4 structure and its receptor binding mechanism determined by a combined cross-linking coupled to mass spectrometry and molecular dynamics approach
AU - Henry, Nicolas
AU - Krammer, Eva Maria
AU - Stengel, Florian
AU - Adams, Quentin
AU - Van Liefferinge, François
AU - Hubin, Ellen
AU - Chaves, Rui
AU - Efremov, Rouslan
AU - Aebersold, Ruedi
AU - Vandenbussche, Guy
AU - Prévost, Martine
AU - Raussens, Vincent
AU - Deroo, Stéphanie
N1 - Funding Information:
E.-M.K. and S.D. are postdoctoral researchers, and M.P. and V.R. are senior research associates of the Fonds de la Recherche Scientifique de Belgique (F.R.S.-FRNS). V.R. and S.D. acknowledge support from the F.R.S.-FNRS (PDR #70214.12) and the SAO-FRA (grant S#14025). N.H. was supported by a FRIA doctoral fellowship. F.S. acknowledges funding from the Wellcome Trust (Grant 095951) and the German Science Foundation Emmy Noether Programme (STE 2517/1-1). R.A. is supported by ERC AdG “Proteomics v.3.0” (grant 233226) and AdG 679821 “Proteome in context”. E.H. was supported by a FWO doctoral fellowship. Computational resources were provided by the Consortium des Équipements de Calcul Intensif (CÉCI), and the F.R.S.-FNRS under convention 2.5020.11, together with the supercomputing facilities of the Université Catholique de Louvain (CISM/UCL) and the ULB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
S#14025).N.H.wassupportedbyaFRIAdoctoral fellowship.F.S.acknowledgesfundingfromthe WellcomeTrust(Grant095951)andtheGerman ScienceFoundationEmmyNoetherProgramme (STE2517/1-1).R.A.issupportedbyERCAdG “Proteomicsv.3.0”(grant233226)andAdG 679821“Proteomeincontext”.E.H.wassupported byaFWOdoctoralfellowship.Computational resourceswereprovidedbytheConsortiumdes ÉquipementsdeCalculIntensif(CE ´CI),andtheF.R. S.-FNRSunderconvention2.5020.11,together withthesupercomputingfacilitiesoftheUniversite ´ CatholiquedeLouvain(CISM/UCL)andtheULB. Thefundershadnoroleinstudydesign,data collectionandanalysis,decisiontopublish,or preparationofthemanuscript.
Publisher Copyright:
© 2018 Henry et al. http://creativecommons.org/licenses/by/4.0/
PY - 2018/6
Y1 - 2018/6
N2 - 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 comprehensive 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 dynamics simulations of the dimerized and lipidated apoE4 monomeric conformations revealed an elongation of the apoE N-terminal domain, whereby helix 4 is rearranged, together with Arg172, into a proper orientation essential for lipoprotein receptor association. Overall, our results show how apoE4 adapts its conformation for the recognition of the low density lipoprotein receptor and we propose a novel mechanism of activation for apoE4 that is based on accessibility and remodeling of the receptor binding region.
AB - 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 comprehensive 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 dynamics simulations of the dimerized and lipidated apoE4 monomeric conformations revealed an elongation of the apoE N-terminal domain, whereby helix 4 is rearranged, together with Arg172, into a proper orientation essential for lipoprotein receptor association. Overall, our results show how apoE4 adapts its conformation for the recognition of the low density lipoprotein receptor and we propose a novel mechanism of activation for apoE4 that is based on accessibility and remodeling of the receptor binding region.
UR - http://www.scopus.com/inward/record.url?scp=85049380724&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1006165
DO - 10.1371/journal.pcbi.1006165
M3 - Article
C2 - 29933361
AN - SCOPUS:85049380724
VL - 14
JO - PLoS Computational Biology
JF - PLoS Computational Biology
SN - 1553-734X
IS - 6
M1 - e1006165
ER -