ArticleProceedings of the National Academy of Sciences of the United States of America2023
Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 40 citations in OpenAlex.
- ApoE4 as a Therapeutic Target in Epilepsy: From Pathogenic Mechanisms to Precision Medicine.CNS neuroscience & therapeutics · 2026Review
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- Role of apolipoprotein E4 in alzheimer's disease pathogenesis and emerging therapeutic strategies.Metabolic brain disease · 2025Review
- APOE Genotype Difference in the Biphasic Modulation of Amyloid-β Aggregation by Direct Binding and Lowering the Nucleation Barrier.Biomacromolecules · 2025Article
- TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Article
- The dimerization domain of SARS-CoV-2 nucleocapsid protein is partially disordered and forms a dynamic high-affinity dimer.Cell reports. Physical science · 2025Article
- Model-free photon analysis of diffusion-based single-molecule FRET experiments.Nature communications · 2025Article
- Molecular Dynamics of Apolipoprotein Genotypes APOE4 and SNARE Family Proteins and Their Impact on Alzheimer's Disease.Life (Basel, Switzerland) · 2025Article
- Accounting for Fast vs Slow Exchange in Single Molecule FRET Experiments Reveals Hidden Conformational States.Journal of chemical theory and computation · 2024Article
- Structural diversity of Alzheimer-related protein aggregations revealed using photothermal ratio-metric micro-spectroscopy.Biomedical optics express · 2024Article
- Structural dynamics of the intrinsically disordered linker region of cardiac troponin T.bioRxiv : the preprint server for biology · 2024Article
- Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Review
- Multifaceted roles of APOE in Alzheimer disease.Nature reviews. Neurology · 2024Review
- Apolipoprotein E in Alzheimer's disease trajectories and the next-generation clinical care pathway.Nature neuroscience · 2024Review
- Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation.Research square · 2024Article
- Accounting for fast vs slow exchange in single molecule FRET experiments reveals hidden conformational states.bioRxiv : the preprint server for biology · 2024Article
- The molecular basis for cellular function of intrinsically disordered protein regions.Nature reviews. Molecular cell biology · 2024Review
- Biophysical Mechanism of Allosteric Regulation of Actin Capping Protein.Journal of molecular biology · 2023Article
- In Silico Structural Analysis Exploring Conformational Folding of Protein Variants in Alzheimer's Disease.International journal of molecular sciences · 2023Article
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer's disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically detailed model of monomeric ApoE4 and probe the effect of lipid association. Importantly, our approach overcomes previous limitations by allowing us to work at picomolar concentrations where only the monomer is present. Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids. Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble. Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein.
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