Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification

Zannis, Vassilis I.; Breslow, Jan L.

doi:10.1021/bi00507a059

Cited by 521 publications

(228 citation statements)

References 54 publications

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“…The other polypeptides C1/C3 and C2/C4 are located in a chloroplastic membrane as shown by subcellular fractionation (Granier eta!., 1986) speculate that these two proteins are two products of the same gene. This may occur if one or both gene products undergo a post-translational modification such as phosphorylation or glycosylation which are known to induce changes in isoelectric point and even in relative molecular mass (Anderson and Anderson, 1979;Zannis and Breslow, 1981). These two proteins are cytoplasmically-encoded, as shown by comparing alloplasmic lines (table 1).…”

Section: Resultsmentioning

confidence: 99%

Variability of 3 cytoplasmically encoded proteins in the Triticum genus

et al. 1988

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Section: Resultsmentioning

confidence: 99%

Variability of 3 cytoplasmically encoded proteins in the Triticum genus

et al. 1988

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“…The N-terminal domain consists of a four-helix 22 kDa N-terminal region (Wilson et al, 1991) that mediates the binding of apoE to LDLR family members, such as LRP (Innerarity et al, 1983), as well as to heparin (Weisgraber et al, 1986) and to HSPGs (Mahley and Ji, 1999) The 10 kDa COOH-terminal domain facilitates the association of apoE with various lipoproteins (Weisgraber and Xi, 1990;Westerlund and Weisgraber, 1993), and is also responsible for the self-association of lipid-free apoE This latter region also contains a second heparin binding site (Weisgraber et al, 1986) With regard to functional consequences of these interactions, it is currently accepted that in order to mediate catabolism of lipoprotein remnants containing apoE, this protein initially interacts with cell surface HSPG, via its heparin binding site(s), and is then transferred to LRP for internalization. The importance of apoE in the pathophysiologic responses of humans is indicated by many studies in which the nature of the distributions of the three common alleles for apoE, viz., E2, E3, and E4 (Zannis and Breslow, 1981), have been associated with risk of central nervous system diseases, e.g., Alzheimer's disease (AD) (Strittmatter et al, 1993), and coronary artery diseases. Such tendencies are likely due to the altered lipid profiles found in those patients that express these different forms of apoE (Dallongeville et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

N-methyl-d-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein

et al. 2008

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The effects of a synthetic apoE1 peptide, viz., residues 133-149 (apoE[133-149]), a mimetic that comprises the apoE receptor-binding domain, on N-methyl-D-aspartate (NMDA)/glycine-induced ion flow through NMDA receptor (NMDAR) channels, has been investigated. The activity of apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] was found to depend on the low density lipoprotein receptor-related protein (LRP). Competition experiments with receptor associated protein (RAP) and activated α 2 macroglobulin (α 2 M*), two proteins that compete for apoE binding to LRP, demonstrate that apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] inhibition of NMDAR function is mediated at a locus in LRP that overlaps with the binding sites of RAP and α 2 M*. A co-receptor of LRP, cell-surface heparin sulfate proteoglycan, did not function in this system. Additional electrophysiology experiments demonstrated that the inhibitory potency of apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] was 3-fold greater for NMDAR-transfected wild-type Chinese Hamster ovary (CHO) cells compared with NMDAR-transfected CHO cells deficient in LRP. Studies with truncation and replacement variants of the apoE peptide demonstrated that the NMDAR-inhibitory properties of these peptides correlate with their binding affinities for LRP. These novel results indicate that apoE functions as an inhibitor of NMDAR ion channels indirectly via LRP, and are suggestive of a participatory role for LRP in NMDAR-based neuropathies.

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“…According to the Zannis-Breslow model, assuming three alleles at a single gene locus (10)(11)(12), there are six phenotypes of apo-E expressed: three homozygous (E2/2, E3/3, and E4/4) and three heterozygous (E2/3, E2/4, and E3/4). Subjects with type III hyperlipoproteinemia are ofthe E2/2 homozygous phenotype (2,3,(10)(11)(12).…”

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confidence: 99%

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

Rall¹,

Weisgraber²,

Innerarity³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

302

147

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The three major isoforms of human apolipoprotein E (apo-E2, -E3, and -E4) are coded for by three alleles (E2, E3, and E4) 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 ofapo-E3 or -E4. Subjects with the genetic disorder type m hyperlipoproteinemia are phenotypically homozygous for apo-E2, but the binding activity of apo-E to the fibroblast receptor differs considerably from one type HI individual to another. We therefore undertook a partial comparative sequence analysis of apo-E2 from three type ]II subjects whose apo-E displayed this heterogeneity. The subject with the poorest binding apo-E2 was genotypically homozygous for an apo-E allele (£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 (E2*); cysteine was found at site A and at a new site (site C, residue 145). The £2* allele specifies a protein that has arginine at site B (residue 158); the e2 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 E2 allele and one E2* allele. The intermediate binding activity of apo-E2 from this subject resulted from having a mixture of severely defective apo-E (specified by E2) and slightly defective apo-E (specified by E2*). (13,14), demonstrating that the alleles controlling the expression of these isoforms are the structural genes for apo-E. The E2, E3, and E4 isoforms differ by virtue ofamino acid substitutions at two sites in the protein, involving cysteine/arginine interchanges. The E3 isoform has a cysteine at site A (residue 112) and an arginine at site B (residue 158). However, the E2 isoform from a type III subject has cysteine at both sites (14). The E4 isoform lacks cysteine entirely and contains arginine at both residues 112 and 158, as determined by partial sequence analysis (unpublished data). Therefore, the E2 and E4 isoforms each differ from E3 by a single amino acid substitution (13,14). It has been shown that apo-E2 from subjects with type III hyperlipoproteinemia does not bind to the apo-B,E [low density lipoprotein (LDL)] receptors of human fibroblasts as well as E3 and E4, which are equally active (15, 16). Furthermore, it has been shown that the substitution at site B (cysteine for arginine) in the sequence ofthe E2 isoform is...

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Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification

Cited by 521 publications

References 54 publications

Variability of 3 cytoplasmically encoded proteins in the Triticum genus

Variability of 3 cytoplasmically encoded proteins in the Triticum genus

N-methyl-d-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein

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

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