ArticlePLoS computational biology2018
Lipidated apolipoprotein E4 structure and its receptor binding mechanism determined by a combined cross-linking coupled to mass spectrometry and molecular dynamics approach.
Article in PLoS computational biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- Revealing a Novel Landscape of the Association Between Blood Lipid Levels and Alzheimer's Disease: A Meta-Analysis of a Case-Control Study.Frontiers in aging neuroscience · 2019Pooled it
- ApoE lipidation state directs immunometabolic reprogramming of human microglia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.Molecular neurodegeneration · 2026Review
- A Robust Serum Proteomic Signature of the E2 Allele of Apolipoprotein E.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- APOE Lipoprotein Particles: Pathophysiology, Therapy, and the Crosstalk in Alzheimer's Disease and Cardiovascular Disease.Molecular neurobiology · 2025Review
- APOE Genotype Difference in the Biphasic Modulation of Amyloid-β Aggregation by Direct Binding and Lowering the Nucleation Barrier.Biomacromolecules · 2025Article
- Structural analyses define the molecular basis of clusterin chaperone function.Nature structural & molecular biology · 2025Article
- The cell biology of APOE in the brain.Trends in cell biology · 2024Review
- Molecular modeling of apoE in complexes with Alzheimer's amyloid-β fibrils from human brain suggests a structural basis for apolipoprotein co-deposition with amyloids.Cellular and molecular life sciences : CMLS · 2023Article
- Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The role of ApoE-mediated microglial lipid metabolism in brain aging and disease.Immunometabolism (Cobham, Surrey) · 2023Review
- ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis.Antioxidants (Basel, Switzerland) · 2022Article
- APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer's disease pathology and brain diseases.Molecular neurodegeneration · 2022Review
- Endogenous Human Proteins Interfering with Amyloid Formation.Biomolecules · 2022Review
- Interpretable artificial intelligence and exascale molecular dynamics simulations to reveal kinetics: Applications to Alzheimer's disease.Current opinion in structural biology · 2022Review
- Structural biology of cell surface receptors implicated in Alzheimer's disease.Biophysical reviews · 2022Review
- The LDL receptor binding domain of apolipoprotein E directs the relative orientation of its C-terminal segment in reconstituted nascent HDL.Biochimica et biophysica acta. Biomembranes · 2021Article
- Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles.ACS nano · 2021Article
- Selective cross-linking of coinciding protein assemblies by in-gel cross-linking mass spectrometry.The EMBO journal · 2021Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 4 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.