ArticleProceedings of the National Academy of Sciences of the United States of America2017
Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 59 citations in OpenAlex.
- Computational Selectivity Analysis of Aptamer toward Oxidized Low-Density Lipoprotein.ACS omega · 2026Article
- XL-MS and De Novo Protein Design Identified a Common Motif for TREM2 Binding.bioRxiv : the preprint server for biology · 2026Article
- Genome-wide association study and pathway analysis of healthy aging in Super Seniors.GeroScience · 2026Article
- Conformational features of guinea pig apolipoprotein E offer insights into functioning of human apolipoprotein E.Archives of biochemistry and biophysics · 2025Article
- Discovery of an ApoE4-targeted small-molecule SirT1 enhancer for the treatment of Alzheimer's disease.Scientific reports · 2025Article
- Neuronal Stem Cells from Late-Onset Alzheimer Patients Show Altered Regulation of Sirtuin 1 Depending on Apolipoprotein E Indicating Disturbed Stem Cell Plasticity.Molecular neurobiology · 2024Article
- Molecular dynamics simulation of apolipoprotein E3 lipid nanodiscs.Biochimica et biophysica acta. Biomembranes · 2024Article
- Article
- Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate.Molecular neurodegeneration · 2023Article
- Apolipoprotein E (APOE) Haplotypes in Healthy Subjects from Worldwide Macroareas: A Population Genetics Perspective for Cardiovascular Disease, Neurodegeneration, and Dementia.Current issues in molecular biology · 2023Article
- Orthogonal analysis of variants in APOE gene usingFrontiers in bioinformatics · 2023Article
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer's disease?Therapeutic advances in chronic disease · 2022Review
- Apolipoprotein E and Atherosclerosis.Current atherosclerosis reports · 2021Review
- Genetic Regulatory Networks of Apolipoproteins and Associated Medical Risks.Frontiers in cardiovascular medicine · 2021Review
- The Links between Cardiovascular Diseases and Alzheimer's Disease.Current neuropharmacology · 2021Review
- ApoE and ApoE Nascent-Like HDL Particles at Model Cellular Membranes: Effect of Protein Isoform and Membrane Composition.Frontiers in chemistry · 2021Article
- APOE in the normal brain.Neurobiology of disease · 2020Review
- Protein-Nanoparticle Interaction: Corona Formation and Conformational Changes in Proteins on Nanoparticles.International journal of nanomedicine · 2020Review
- Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-β peptide, and it is associated with increased incidence of cardiovascular and Alzheimer's disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen-deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution. We determined the positions, dynamics, and stabilities of the helical segments in these two proteins, in their normal tetrameric state and in mutation-induced monomeric mutants. Consistent with prior X-ray crystallography and NMR results, the N-terminal domain contains four α-helices, 20 to 30 amino acids long. The C-terminal domain is relatively unstructured in the monomeric state but forms an α-helix ∼70 residues long in the self-associated tetrameric state. Helix stabilities are relatively low, 4 kcal/mol to 5 kcal/mol, consistent with flexibility and facile reversible unfolding. Secondary structure in the tetrameric apoE3 and E4 isoforms is similar except that some helical segments in apoE4 spanning residues 12 to 20 and 204 to 210 are unfolded. These conformational differences result from the C112R substitution in the N-terminal helix bundle and likely relate to a reduced ability of apoE4 to form tetramers, thereby increasing the concentration of functional apoE4 monomers, which gives rise to its higher lipid binding compared with apoE3.
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Registered trials
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