Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects.

Rall, S C; Weisgraber, K H; Innerarity, T L; Mahley, R W

doi:10.1073/pnas.79.15.4696

Cited by 345Lipoproteins and Cardiovascular HealthAlzheimer's disease research and treatmentsCholesterol and Lipid Metabolism

Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects.

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Rall, S C, Weisgraber, K H, Innerarity, T L, Mahley, R W·1982·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.79.15.4696PMC PMC346743

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Abstract

The three major isoforms of human apolipoprotein E (apo-E2, -E3, and -E4) are coded for by three alleles (epsilon 2, epsilon 3, and epsilon 4) which have a common genetic locus. Previously, we demonstrated that E2, E3, and E4 differ in primary structure from one another at two substitution sites, site A (residue 112) and site B (residue 158). At sites A/B, apo-E2, -E3, and -E4 contain cysteine/cysteine, cysteine/arginine, and arginine/arginine, respectively. We demonstrated that the substitution of cysteine for arginine at site B is at least partly responsible for the defective binding of apo-E2 to human fibroblast low density lipoprotein receptors, compared to the normal binding activity of apo-E3 or -E4. Subjects with the genetic disorder type III hyperlipoproteinemia are phenotypically homozygous for apo-E2, but the binding activity of apo-E to the fibroblast receptor differs considerably from one type III individual to another. We therefore undertook a partial comparative sequence analysis of apo-E2 from three type III subjects whose apo-E displayed this heterogeneity. The subject with the poorest binding apo-E2 was genotypically homozygous for an apo-E allele (epsilon 2); cysteine was found at sites A and B. The subject with the most active apo-E2 was genotypically homozygous for an apo-E allele (epsilon 2); cystine was found at site A and at a new site (site C, residue 145). The epsilon 2 allele specifies a protein that has arginine at site B (residue 158); the epsilon 2 allele specifies a protein that has arginine at site C (residue 145). Therefore, the two alleles differ from one another by cysteine/arginine interchanges at two positions, sites B and C. The third subject, whose apo-E2 displayed binding activity intermediate between the activities of the other two, was genotypically heterozygous, having one epsilon 2 allele and one epsilon 2 allele. The intermediate binding activity of apo-E2 from this subject resulted from having a mixture of severely defective apo-E (specified by epsilon 2) and slightly defective apo-E (specified by epsilon 2).

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Three apo E2 variants have been described, each differing from apo E3 by a single amino acid substitution.
“Three variants ofapo E2 have been described.Each ofthese differs from apo E3 by a single amino acid substitution (6, 12- 14).”
From Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. (1987) · cites this paper as [14]
The most common apo E2 has a 158 Arg-to-Cys mutation, while 145 Arg-to-Cys and 146 Lys-to-Gln mutations have also been reported in type III hyperlipoproteinemia.
“The most common has a mutation of 158 Arg --Cys (13), but mutations of 145 Arg -* Cys (14) and 146 Lys --Gln (6) have also been reported in individuals with type III hyperlipoproteinemia.”
From Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. (1987) · cites this paper as [14]
Homozygosity and heterozygosity for apoE3[R145C] are associated with severe type III HLP.
“Homozygosity and heterozygocity for the apoE variant apoE3[R145C] has also been associated with severe type III HLP [30], [31].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [30]
The 22-kDa domain of lipid-bound apoE3[R145C] has 48% reduced HSPG binding capacity compared to apoE3-22kDa.
“and the 22-kDa domain of lipid-bound apoE3[R145C] has 48% reduced HSPG binding capacity compared to apoE3-22kDa [30], [32].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [30]
Lipid-bound apoE3[R145C] has 55% reduced LDL receptor binding capacity compared to apoE3.
“Binding studies showed that lipid-bound apoE3[R145C] has 55% reduced LDL receptor binding capacity compared to apoE3”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [30]

These apoE3 variants maintain their ability to predispose to type III HLP and do so in a dominant fashion, unlike apoE2.
“Still, these variants not only maintain their ability to predispose to type III HLP, but also do so in a dominant fashion, unlike apoE2 [22], [26], [30], [31], [33], [34], [35].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [30]
All apoE3 variants studied here demonstrate stronger LDL receptor binding compared to wild-type apoE2.
“In contrast, all apoE3 variants studied here demonstrate stronger LDL receptor binding compared to wild-type apoE2 [28], [30], [34], [35].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [30]
Heterozygosity for apoE2(145 Arg→Cys), apoE2(146 Lys→Gln), or apoE2-Christchurch(136 Arg→Ser) is associated with type III hyperlipoproteinemia.
“While heterozygosity for three further mutants (apoE2(145 Arg→Cys) (32, 33), apoE2(146 Lys→Gln) (34), or apoE2-Christchurch(136 Arg→Ser) (18, 33)) is associated with type III hyperlipoproteinemia, there are no family studies to ascertain whether these variants also demonstrate a dominant mode of inheritance.”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [32]
R145C is always in phase with APOE ε3 and R150H is always in phase with APOE ε2.
“Prior studies [7][8][9] and Alzheimer Disease Sequencing Project (ADSP) data have shown that R145C is always in phase with ε3 and R150H is always in phase with ε2.”
From Association of African Ancestry–Specific APOE Missense Variant R145C With Risk of Alzheimer Disease (2023) · cites this paper as [8]

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Identification of a new structural variant of human apolipoprotein E, E2(Lys146 leads to Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype.
Rall, S. C., Weisgraber, K. H., Innerarity, T. L., Bersot, T. P., Mahley, R. W., & Blum, C. B. (1983) · Journal of Clinical Investigation · doi:10.1172/jci111085 · Cited by 141 · see citing works
Self-citation
Identification of a New Structural Variant of Human Apolipoprotein E, E2(Lys,46, Gln), in a Type III Hyperlipoproteinemic Subject
Phenotype, T. E., Rall, S. C., Weisgraber, K. H., Innerarity, T. L., Bersot, T. P., Mahley, R. W., Gladstone Foundation, Blum, C. B., Department Of Medicine, & Arteriosclerosis, T. (1983)
Self-citation

Authors: Rall, S. C., Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W.
ORCID: Mahley, R W
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1982-08
Volume: 79
Issue: 15
Pages: 4696-4700
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.79.15.4696
PMC: PMC346743
OpenAlex: W2081151510
Cited by: 345
References: 16
Citations by year: 2024: 7 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 6 · 2014: 4 · 2013: 3 · 2012: 7
FWCI: 54.05
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords: apolipoprotein E, type III hyperlipoproteinemia, LDL receptor, apolipoprotein E isoforms, site-directed mutagenesis, receptor binding activity, genetic polymorphism
MeSH terms: Alleles, Amino Acid Sequence, Apolipoproteins, Apolipoproteins E, Genes, Humans, Hyperlipoproteinemia Type III, Receptors, Cell Surface, Low Density Lipoprotein Receptor-Related Protein-1

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Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects.

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