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Cited by 113Lipid Membrane Structure and BehaviorProtein Interaction Studies and Fluorescence AnalysisProtein Structure and Dynamics

Lipid Binding-induced Conformational Change in Human Apolipoprotein E

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Saito, Hiroyuki, Dhanasekaran, Padmaja, Baldwin, Faye, Weisgraber, Karl H., Lund-Katz, Sissel, Phillips, Michael C.·2001·Journal of Biological Chemistry
DOI 10.1074/jbc.m106337200
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Abstract

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.

    “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]

    The ApoE Conformation on Emulsion section reports that apoE4 adopts different lipid-bound conformations and discusses their effects on LDL-receptor binding. The Effects of Particle Size section also discusses interaction between its N- and C-terminal domains. Neither section establishes that variants with lower thermodynamic stability have altered interdomain interactions and defective physiological functions; the measured thermodynamics concern lipid binding, not protein stability. Page numbers are unavailable in our copy. (LLM, conf=0.84)

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  • The C-terminal domain of apoE contains amphipathic α-helices involved in binding to lipoproteins with high affinity.

    “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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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.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2001-11
Volume
276
Issue
44
Pages
40949-40954
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m106337200
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
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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