Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112
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Human apolipoprotein (apo) E occurs as three common isoforms (apoE4, E3, and E2), all of which influence plasma cholesterol levels. Although both apoE4 and E3 bind with equal effectiveness to the low density lipoprotein receptor, they associate preferentially with different classes of plasma lipoproteins: apoE4 with very low density lipoproteins, apoE3 with high density lipoproteins. The primary structure of apoE3 differs from that of apoE4 at only a single site; apoE3 has its sole cysteine residue at position 112, while apoE4 contains arginine at position 112 and completely lacks cysteine. The present study investigated how this structural difference between apoE4 and E3 determines their distribution among plasma lipoproteins, and analyzed the role of the disulfide-linked heterodimer apoE-A-II (which apoE4 cannot form) in determining the distribution. Human plasma was incubated with 125I-labeled apoE, and lipoproteins were separated by agarose chromatography. Both apoE3 that had been reduced and alkylated with iodoacetamide and apoE3-A-II distributed with high density lipoproteins, indicating that a combination of an inherent property of the monomeric apoE3 structure and apoE-A-II formation account for distribution of apoE3 to the high density lipoproteins. Cysteamine modification of apoE3 resulted in an apoE4-like distribution, demonstrating that a positive charge at position 112 determined the apoE4 distribution and that the effect was not exclusively due to the presence o…
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The difference in lipoprotein distribution between apoE3 and apoE4 is due to the polymorphism at position 112, where arginine directs the apoprotein more to VLDL.
“The difference in lipoprotein distribution between apoE3 and apoE4 has been shown to be due to the polymorphism at position 112 (21), where the presence of an arginine directs the apoprotein more to the VLDL.”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [21]
The polymorphism at position 112 affects the affinity of apoE for lipoproteins, with apoE4 preferring VLDL to HDL relative to apoE3, which prefers HDL to VLDL.
“It has been demonstrated previously that the polymorphis at position 112 affects the affinity of apoE for lipoproteins, with apoE4 (arginine 112) preferring VLDL to HDL relative to apoE3, which prefers HDL to VLDL (21).”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [21]
The three common ApoE isoforms differ at two residues: ApoE2 carries Cys112/Cys158, ApoE3 carries Cys112/Arg158, and ApoE4 carries Arg112/Arg158.
“The three isoforms differ at two residues: ApoE2 carries Cys112/Cys158, ApoE3 carries Cys112/Arg158, and ApoE4 carries Arg112/Arg158.”
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- Authors
- Weisgraber, K. H.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Weisgraber, K H
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 1990-08
- Volume
- 31
- Issue
- 8
- Pages
- 1503-1511
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2155559959
- Cited by
- 304
- References
- 26
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 4 · 2020: 7 · 2019: 10 · 2018: 8 · 2017: 12 · 2016: 7 · 2015: 5 · 2014: 6 · 2013: 9 · 2012: 5
- FWCI
- 14.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E, apolipoprotein E isoforms, APOE ε4, APOE3, APOE2, serum lipoproteins, high-density lipoprotein, VLDL, disulfide bonds, serum cholesterol, LDL receptor
- MeSH terms
- Apolipoproteins E, Arginine, Cysteine, Humans, Lipoproteins, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Lipoproteins, IDL
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