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The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia

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Horie, Y, Fazio, S, Westerlund, J R, Weisgraber, K H, Rall, S C·1992·Journal of Biological Chemistry
DOI 10.1016/s0021-9258(18)46040-1
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Abstract

Type III hyperlipoproteinemia typically is associated with homozygosity for apolipoprotein (apo) E2(Arg158----Cys). Dominant expression of type III hyperlipoproteinemia associated with apoE phenotype E3/3 is caused by heterozygosity for a human apoE variant, apoE3(Cys112----Arg, Arg142----Cys). However, this apoE3 variant was not separable from the normal apoE3 in these patients' plasma because the two proteins have identical amino acid composition, charge, and molecular weight. Therefore, to determine the functional characteristics of this protein, we used recombinant DNA techniques to produce this apoE variant in bacteria. We also produced a non-naturally occurring variant, apoE(Arg142----Cys), that had only the cysteine substituted at residue 142. These two apoE variants were purified from cell lysates of the transfected Escherichia coli by ultracentrifugal flotation in the presence of phospholipid, by gel filtration chromatography, and by heparin-Sepharose chromatography. Both Cys142 apoE variants bound to lipoprotein receptors on human fibroblasts with only about 20% of normal binding activity. Therefore, cysteine at residue 142, not arginine at residue 112, is responsible for the decreased receptor binding activity of the variants. Cysteamine treatment and removal of the carboxyl-terminal domain had little effect on the binding activity, whereas both modulate the receptor binding activity of apoE2(Arg158----Cys). The mutation at residue 142 decreased the binding activit…

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  • Both apoE Leiden and another apoE variant that shows preferential in vitro association with VLDL are found in much higher concentrations compared with normal apoE in affected subjects' VLDL, at a ratio of 4:1 or higher in the former and 3:1 in the latter.

    “In contrast, both apoE Leiden and another apoE variant that shows a preferential in vitro association with VLDL (22) are found in much higher concentrations compared with normal apoE in affected subjects' VLDL, at a ratio of 4:1 or higher in the former instance (12) and 3:1 in the latter instance (22).”

    From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [22]

  • There are probably other properties of apoE or additional factors that help determine whether the mode of inheritance of type III hlp will be dominant or recessive.

    “Instead, it is probably that there are other properties of apoE or additional factors that help determine whether the mode of inheritance of type III hlp will be dominant or recessive (3, 12, 22).”

    From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [22]

  • Rare APOE variants associated with dominant type III HLPs include APOE2 Heidelberg (Arg136Cys), APOE2 Christchurch (Arg136Ser), APOE2 (Arg142Cys), APOE2 (Arg142Leu), APOE2 (Lys146Gln), and APOE1 Harrisburg (Lys146Glu).

    “Rare APOE variants associated with dominant type III HLPs include single-nucleotide substitutions at APOE2 Heidelberg (Arg136Cys)47), APOE2 Christchurch (Arg136Ser)26, 48), APOE2 (Arg142Cys)49, 50), APOE2 (Arg142Leu)51), APOE2 (Lys146Gln)45), and APOE1 Harrisburg (Lys146Glu)52, 53) (Table 2, Fig.5).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [49]

  • A variety of rare mutations in the 136-147 region of apoE are associated with a dominant mode of inheritance of type III HLP that is expressed at an early age.

    “A variety of rare mutations in the 136-147 region of apoE are associated with a dominant mode of inheritance of type III HLP that is expressed at an early age ( 7,8,12,13 ).”

    From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [13]

  • DMPC proteoliposomes containing the R142C variant expressed in bacteria had reduced binding affinity for the LDL receptor, a receptor blocking monoclonal antibody, and heparin based on competition experiments.

    “DMPC proteoliposomes containing the R142C variant expressed in bacteria had reduced binding affi nity for the LDL receptor, a receptor blocking monoclonal antibody, and heparin based on competition experiments ( 13 ).”

    From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [13]

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Authors
Horie, Y., Fazio, S., Westerlund, J. R., Weisgraber, K. H., & Rall, S. C.
Affiliations
University of California, San Francisco (US)
ORCID
Fazio, S
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1992-01
Volume
267
Issue
3
Pages
1962-1968
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/s0021-9258(18)46040-1
OpenAlex
W1582053154
Cited by
94
References
6
Citations by year
2026: 1 · 2025: 3 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2016: 1 · 2015: 1 · 2014: 5 · 2013: 2 · 2012: 1
FWCI
10.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
apolipoprotein E, type III hyperlipoproteinemia, apolipoprotein E2, apolipoprotein E3, VLDL, dominant inheritance
MeSH terms
Amino Acid Sequence, Apolipoproteins E, Binding Sites, Binding, Competitive, Cloning, Molecular, Cysteine, Escherichia coli, Genetic Vectors, Heparin, Homozygote, Humans, Hyperlipoproteinemia Type III, Kinetics, Receptors, LDL, Recombinant Proteins, Genetic Variation

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