Comparison of the stabilities and unfolding pathways of human apolipoprotein E isoforms by differential scanning calorimetry and circular dichroism.
Abstract
Differential scanning calorimetry and circular dichroism experiments were performed to study structural differences among the common isoforms of human apolipoprotein E (apoE2, apoE3, and apoE4) and their N-terminal, 22-kDa fragments. Here, we examine thermodynamic properties that characterize the structural differences among isoforms, and also differences in their unfolding behavior. The 22-kDa fragments and their full-length counterparts were found to exhibit similar differences in thermal stability (apoE4<apoE3<apoE2; T(max) approximately 52<56<59 degrees C, respectively). Helical contents at the onset and completion of denaturation (as monitored calorimetrically) were about 51% and 35%, respectively, for 22-kDa apoE3. As much as 70% of the unfolding enthalpy for 22-kDa apoE3 could be due to disruption of alpha-helix. The monomeric 22-kDa fragments unfold differently, with both apoE3 and apoE4 exhibiting unfolding intermediates, whereas apoE2 unfolds according to a two-state mechanism. Interactions with the C-terminal domain appear to destabilize the N-terminal domains in full-length apoE2 and apoE3, but less so for full-length apoE4. Self-association of full-length apoE at higher concentrations (1.5-2.5 mg/ml), as well as interaction of full-length apoE with phospholipid, enhances thermal stability. Cooperative changes in secondary structure, as monitored by circular dichroism, begin near 37 degrees C for full-length apoE3 and apoE4, indicating that full-length apoE3 and a…
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Differences in function and disease predisposition are established between apoE3 and apoE2, although these two variants differ only at a single amino acid at position 158.
“Similarly, differences in function and disease predisposition are established between apoE3 and apoE2 although these two variants differ only at a single amino acid at position 158 [65], [72], [74].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [72]
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- Authors
- Acharya, P., Segall, M. L., Zaiou, M., Morrow, J., Weisgraber, K. H., Phillips, M. C., Lund-Katz, S., & Snow, J.
- Affiliations
- University of the Sciences (US)
- Children's Hospital of Philadelphia (US)
- Gladstone Institutes (US)
- Corresponding author
- Snow, Julian
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2002-09
- Volume
- 1584
- Issue
- 1
- Pages
- 9-19
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W2059995793
- Cited by
- 82
- References
- 6
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 5 · 2014: 1 · 2013: 2 · 2012: 3
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL056083, HL-56083)
- 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
- apolipoprotein E, APOE isoforms, APOE2, APOE3, APOE ε4, thermal stability, protein unfolding, unfolding intermediates, two-state unfolding, alpha-helix content, N-terminal fragment, self-association, phospholipid interactions, APOE polymorphism, lipid transport, neurological function
- MeSH terms
- Apolipoproteins E, Calorimetry, Differential Scanning, Circular Dichroism, Humans, Molecular Weight, Protein Denaturation, Protein Structure, Secondary, Protein Folding, Protein Isoforms, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
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