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Cited by 40Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismLipid metabolism and disorders

Two apolipoprotein E5 variants illustrate the importance of the position of additional positive charge on receptor-binding activity

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Wardell, MR, Rall, SC, Schaefer, EJ, Kane, JP, Weisgraber, KH·1991·Journal of Lipid Research
DOI 10.1016/s0022-2275(20)42076-0
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Abstract

Apolipoprotein (apo) E polymorphism has a significant effect on plasma cholesterol and low density lipoprotein cholesterol concentrations. The association of two apoE5 isoforms with elevated plasma low density lipoprotein cholesterol levels in two unrelated subjects led us to investigate the primary structures and receptor-binding properties of their apoE. Cysteamine modification and isoelectric focusing demonstrated that the apoE5 isoform from subject 1 did not contain cysteine but that the apoE5 isoform from subject 2 contained one residue of cysteine. The structural mutation in the apoE5 isoform of subject 1 was determined by peptide sequencing. Like apoE4, this variant had arginine at position 112 but differed from apoE4 by the substitution of arginine for proline at position 84. When purified and subjected to a competitive binding assay, this apoE5(84 Pro----Arg, 112 Cys----Arg) variant had the same receptor-binding activity as normal apoE3. Because subject 2 was of Japanese descent and her apoE5 contained one cysteine residue, we suspected that it would contain the lysine-forglutamic acid mutation at position 3 that has been described previously in Japanese subjects. This was confirmed by directly sequencing the first 10 amino acid residues of her apoE. When subjected to the competitive binding assay, the total apoE from subject 2, which consisted of approximately equal amounts of normal apoE3 and apoE5(3 Glu----Lys), had a binding activity of 188%, confirming the previously reported enhanced binding of this variant. These results demonstrate that the enhancement of receptor-binding activity of more basic isoforms of apoE depends on the position at which additional positively charged amino acids are incorporated.

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  • A few rare apo E variants (p.Glu21Lys, p.Pro102Arg, p.Leu270Glu) have been observed in probands with hyperLDLemia, but none co-segregated with hyperLDLemia in the families.

    “a few rare apo E variants (p.Glu21Lys, p.Pro102Arg and, p.Leu270Glu) have been observed in probands with hyperLDLemia (type IIa hyperlipoproteinemia), but none co-segregated with hyperLDLemia in the families (Wardell MR et al. 1991, van den Maagdenberg AM et al. 1993).”

    From Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the<i>APOE</i>p.Leu167del Mutation (2013) · cites this paper as Wardell MR et al. 1991

  • The p.Arg269Gly apo E mutant has been previously reported in a proband with type IIb hyperlipoproteinemia, differing from ADH by elevated plasma triglyceride levels.

    “The p.Arg269Gly apo E mutant has been previously reported in a proband with type IIb hyperlipoproteinemia, differing from ADH by elevated plasma triglyceride levels (Wardell MR et al. 1991).”

    From Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the<i>APOE</i>p.Leu167del Mutation (2013) · cites this paper as Wardell MR et al. 1991

  • APOE5 (Pro84Arg,Cys112Arg) heterozygosity was found in a 54-year-old woman of European descent with elevated LDL cholesterol levels.

    “Furthermore, APOE5 (Pro84Arg,Cys112Arg) heterozygosity was found in a 54-year-old woman of European descent with elevated LDL cholesterol levels113).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [113]

  • The pathogenic mechanisms underlying HLP in patients with apoE5 (Glu3Lys) are presumed to involve downregulation of LDL receptors due to high uptake of lipoproteins containing this apoE mutant.

    “The pathogenic mechanisms underlying HLP in patients with apoE5 (Glu3Lys) are presumed to involve downregulation of low-density lipoprotein (LDL) receptors due to high uptake of lipoproteins containing this apoE mutant [10,11].”

    From A case of lipoprotein glomerulopathy with a rare apolipoprotein E isoform combined with neurofibromatosis type I (2018) · cites this paper as [11]

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Authors
Wardell, M., Rall, S., Schaefer, E., Kane, J., & Weisgraber, K.
Affiliations
University of California, San Francisco (US)
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
1991-03
Volume
32
Issue
3
Pages
521-528
ISSN
0022-2275 (ISSN-L)
DOI
10.1016/s0022-2275(20)42076-0
OpenAlex
W2138870569
Cited by
40
References
8
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2022: 2 · 2021: 2 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 2 · 2012: 1
FWCI
4.55
Type
journal article
Language
en
Open access
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, APOE polymorphism, receptor binding activity, cysteine substitution, arginine substitution, LDL cholesterol, serum cholesterol
MeSH terms
Amino Acids, Apolipoproteins E, Female, Humans, Isoelectric Focusing, Middle Aged, Polymorphism, Genetic, Receptors, Cell Surface, Low Density Lipoprotein Receptor-Related Protein-1

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