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Lipid Binding-induced Conformational Change in Human Apolipoprotein E
Open accessAbstract
Apolipoprotein (apo) E contains two structural domains, a 22-kDa (amino acids 1-191) N-terminal domain and a 10-kDa (amino acids 223-299) C-terminal domain. To better understand apoE-lipid interactions on lipoprotein surfaces, we determined the thermodynamic parameters for binding of apoE4 and its 22- and 10-kDa fragments to triolein-egg phosphatidylcholine emulsions using a centrifugation assay and titration calorimetry. In both large (120 nm) and small (35 nm) emulsion particles, the binding affinities decreased in the order 10-kDa fragment approximately 34-kDa intact apoE4 > 22-kDa fragment, whereas the maximal binding capacity of intact apoE4 was much larger than those of the 22- and 10-kDa fragments. These results suggest that at maximal binding, the binding behavior of intact apoE4 is different from that of each fragment and that the N-terminal domain of intact apoE4 does not contact lipid. Isothermal titration calorimetry measurements showed that apoE binding to emulsions was an exothermic process. Binding to large particles is enthalpically driven, and binding to small particles is entropically driven. At a low surface concentration of protein, the binding enthalpy of intact apoE4 (-69 kcal/mol) was approximately equal to the sum of the enthalpies for the 22- and 10-kDa fragments, indicating that both the 22- and 10-kDa fragments interact with lipids. In a saturated condition, however, the binding enthalpy of intact apoE4 (-39 kcal/mol) was less exothermic and rather similar to that of each fragment, supporting the hypothesis that only the C-terminal domain of intact apoE4 binds to lipid. We conclude that the N-terminal four-helix bundle can adopt either open or closed conformations, depending upon the surface concentration of emulsion-bound apoE.
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“ApoE variants with lower thermodynamic stability and changes in conformational plasticity have been shown to have altered interdomain interactions and defective physiological functions (19, 24 -28).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [26]
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“whereas the C-terminal domain contains amphipathic α-helices that are involved in binding to lipoproteins with high affinity (21, 22).”
From Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study (2008) · cites this paper as [22]
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Metadata
- Authors
- Saito, H., Dhanasekaran, P., Baldwin, F., Weisgraber, K. H., Lund-Katz, S., & Phillips, M. C.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University of California, San Francisco (US)
- Corresponding author
- Phillips, Michael C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 276
- Issue
- 44
- Pages
- 40949-40954
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2006324786
- Cited by
- 113
- References
- 50
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 5 · 2017: 3 · 2015: 1 · 2014: 6 · 2013: 3 · 2012: 5
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-41633, P01HL041633, R01HL056083, HL-56083)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- apolipoprotein E, APOE ε4, lipid binding, conformational change, C-terminal domain, N-terminal domain, four-helix bundle, binding thermodynamics, binding enthalpy, binding entropy, protein-lipid interactions
- MeSH terms
- Apolipoproteins E, Calorimetry, Humans, Protein Conformation, Thermodynamics, Lipid Metabolism
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