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Cited by 204Protein Structure and DynamicsAlzheimer's disease research and treatmentsProtein purification and stability

Apolipoprotein E4 Forms a Molten Globule

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Morrow, Julie A., Hatters, Danny M., Lu, Bin, Höchtl, Peter, Oberg, Keith A., Rupp, Bernhard, Weisgraber, Karl H.·2002·Journal of Biological Chemistry
DOI 10.1074/jbc.m204898200
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Abstract

The amino-terminal domain of apolipoprotein (apo) E4 is less susceptible to chemical and thermal denaturation than the apoE3 and apoE2 domains. We compared the urea denaturation curves of the 22-kDa amino-terminal domains of the apoE isoforms at pH 7.4 and 4.0. At pH 7.4, apoE3 and apoE4 reflected an apparent two-state denaturation. The midpoints of denaturation were 5.2 and 4.3 m urea, respectively. At pH 4.0, a pH value known to stabilize folding intermediates, apoE4 and apoE3 displayed the same order of denaturation but with distinct plateaus, suggesting the presence of a stable folding intermediate. In contrast, apoE2 proved the most stable and lacked the distinct plateau observed with the other two isoforms and could be fitted to a two-state unfolding model. Analysis of the curves with a three-state unfolding model (native, intermediate, and unfolded) showed that the apoE4 folding intermediate reached its maximal concentration ( approximately 90% of the mixture) at 3.75 m, whereas the apoE3 intermediate was maximal at 4.75 m ( approximately 80%). These results are consistent with apoE4 being more susceptible to unfolding than apoE3 and apoE2 and more prone to form a stable folding intermediate. The structure of the apoE4 folding intermediate at pH 4.0 in 3.75 m urea was characterized using pepsin proteolysis, Fourier transform infrared spectroscopy, and dynamic light scattering. From these studies, we conclude that the apoE4 folding intermediate is a single molecule with the characteristics of a molten globule. We propose a model of the apoE4 molten globule in which the four-helix bundle of the amino-terminal domain is partially opened, generating a slightly elongated structure and exposing the hydrophobic core. Since molten globules have been implicated in both normal and abnormal physiological function, the differential abilities of the apoE isoforms to form a molten globule may contribute to the isoform-specific effects of apoE in disease.

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Crossref · 10.1074/jbc.m204898200

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  • The polymorphism at position 112 brings about alterations in the thermodynamic properties of the molecule that may underlie functional changes linked with disease predisposition.

    “This polymorphic variation brings about alterations in the thermodynamic properties of the molecule that may underlie functional changes linked with disease predisposition [61], [65], [71], [72], [73], [74].”

    From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [71]

  • Functional differences between apoE4 and apoE3 have been attributed to altered inter-domain interactions brought about by the polymorphism at position 112 of the N-terminal domain.

    “Specifically, functional differences between apoE4 and apoE3 have been attributed to altered inter-domain interactions brought about by the polymorphism at position 112 of the N-terminal domain.”

    From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [71]

  • ApoE is highly helical, with a labile tertiary structure that can assume structures characteristic of a molten globule.

    “ApoE is highly helical, with a labile tertiary structure that can assume structures characteristic of a molten globule (18).”

    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 [18]

  • ApoE4 is the least stable of all apoE isoforms, denaturing at lower concentrations of urea and at lower temperatures.

    “it is known from in vitro observations that apoE4 is the least stable of all the apoE isoforms: apoE4 denatures at lower concentrations of urea and at lower temperatures”

    From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Morrow et al., 2002

  • The denaturation pattern of apoE4 suggests it can exist as a partially folded intermediate or a molten globule state.

    “the denaturation pattern of apoE4 suggests that it can exist as a partially folded intermediate or a molten globule state (Morrow et al., 2002).”

    From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Morrow et al., 2002

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Authors
Morrow, J. A., Hatters, D. M., Lu, B., Höchtl, P., Oberg, K. A., Rupp, B., & Weisgraber, K. H.
Affiliations
  • Gladstone Institutes (US)
  • Lawrence Livermore National Laboratory (US)
Corresponding author
Weisgraber, Karl H.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2002-12
Volume
277
Issue
52
Pages
50380-50385
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m204898200
OpenAlex
W2016579573
Cited by
204
References
57
Citations by year
2026: 4 · 2025: 10 · 2024: 5 · 2023: 3 · 2022: 11 · 2021: 10 · 2020: 8 · 2019: 8 · 2018: 5 · 2017: 10 · 2016: 9 · 2015: 8 · 2014: 11 · 2013: 4 · 2012: 10
FWCI
2.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (NS35939, R01NS035939)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
Keywords
APOE ε4, molten globule, folding intermediates, urea denaturation, pH-dependent unfolding, N-terminal domain, APOE isoforms, four-helix bundle, FTIR spectroscopy, dynamic light scattering
MeSH terms
Apolipoproteins E, Dimyristoylphosphatidylcholine, Humans, Hydrogen-Ion Concentration, Models, Molecular, Pepsin A, Peptide Fragments, Protein Conformation, Protein Denaturation, Urea, Protein Structure, Secondary, Spectroscopy, Fourier Transform Infrared, Protein Isoforms, Apolipoprotein E3, Apolipoprotein E4

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