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Human apolipoprotein E: Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms

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Dong, L.M., Wilson, C., Wardell, M.R., Simmons, T., Mahley, R.W., Weisgraber, K.H., Agard, D.A.·1994·Journal of Biological Chemistry
DOI 10.1016/s0021-9258(17)31797-0
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Abstract

Human apolipoprotein (apo) E4 (arginine at residue 112) preferentially associates with very low density lipoproteins (VLDL), and apoE3 (cysteine at 112) associates with high density lipoproteins. It has been postulated that the amino-terminal domain, which contains residue 112, influences the lipoprotein preference by interacting with the carboxyl-terminal domain, which contains the lipid-binding region. To delineate the region in the carboxyl-terminal domain mediating lipoprotein binding and involved in isoform preference, we produced truncated apoE3 and apoE4 variants (terminating at residues 251, 260, 266, or 272) in Escherichia coli and assessed them for lipoprotein association. This analysis suggested that residues 260-272 contain important determinants for complete lipoprotein association and isoform preferences. To determine whether positive charge at residue 112 was an absolute requirement for the apoE4 VLDL preference, we compared the distributions of rabbit apoE (equivalent to apoE3, with cysteine at a position corresponding to 112), canine apoE (arginine at the corresponding site), and cysteamine-treated rabbit apoE (cysteine converted to a positively charged residue). Surprisingly, all distributed like human apoE3, suggesting that positive charge at a position corresponding to 112 was not directly responsible for the isoform preference and that other residues in the amino-terminal domain were involved. To determine which residues were involved, the structure of the apoE4 22-kDa fragment (the amino-terminal two-thirds of the molecule) was determined to 2.5 A by x-ray crystallography. Compared with the known four-helix bundle structure of apoE3, the only significant differences in the apoE4 structure were that glutamic acid 109 formed a salt bridge with arginine 112 and that the arginine 61 side chain was displaced to a new position. Site-directed mutagenesis of glutamic acid 109 in apoE3 and arginine 61 in apoE4 demonstrated that the position of the arginine 61 side chain in apoE4 was critical in determining apoE4 lipoprotein distribution, suggesting that arginine 61 interacted with the carboxyl-terminal domain to direct binding to VLDL.

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  • The N-terminal domain of apoE is folded into a four-helix bundle of amphipathic alpha-helices spanning residues 24-164, stabilized by hydrophobic interactions and salt bridges.

    “X-ray crystallography studies showed that the N-terminal domain is folded into a four-helix bundle of amphipathic α-helices spanning residues 24-164 that are stabilized by hydrophobic interactions and salt bridges [15], [16], [17].”

    From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [16]

    The Abstract and the structural description (p. 22358) report an X-ray-derived four-helix bundle in the amino-terminal fragment; the structural description also says residues 1–22 and 165–191 were disordered. Our copy does not specify a 24–164 span or describe the bundle as amphipathic and stabilized by hydrophobic interactions. It identifies a particular salt bridge in apoE4, not salt bridges as a general stabilizing feature of the bundle. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Position 222 is at a flexible loop region of apoE, corresponding to the shoulder of a domain (residues 244-272) hypothesized to bind Aβ and involved in lipid binding.

    “Structurally, position 222 is at a flexible loop region of apoE, corresponding to the shoulder of a domain (residues 244–272) hypothesized to bind Aβ [15] and involved in lipid binding [33].”

    From Discovery of a Missense Mutation (Q222K) of the <i>APOE</i> Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [33]

  • The residue 112 difference indirectly changes a salt bridge and alters the domain-domain interactions between the amino and carboxyl halves of apoE.

    “indirectly this changes a salt bridge and alters the domain-domain interactions of the amino and carboxyl halves of apoE.”

    From Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide (2012) · cites this paper as Dong et al., 1994

  • ApoE2 and apoE3 preferentially adopt an open conformation, while apoE4 preferentially adopts a closed conformation.

    “ApoE2 and apoE3 prefer an open-conformation, whereas apoE4 prefers a closed-conformation due to a difference at amino acid residue 112 between apoE4 (Arg) and apoE2, E3 (Cys) (Dong et al., 1994; Mahley et al., 2009)”

    From Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide (2012) · cites this paper as Dong et al., 1994

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Cites

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Research works printed but not linked: 5

  1. Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Eng- 1. Mahley, R. W. (1988) Science 240,622-630
  2. hild, J., Salvesen, G. S., and Roses, A. D. (1993) Proc. Natl. Acad. Sci.
  3. Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, U. S. A. 90, 1977-1981
  4. Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L.-M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., and 22. Westerlund, J. A,, and Weisgraber, K. H. (1993) J. Biol. Chem. 268, 15745- Roses, A. D. (1993) Proc. Natl. Acud. Sci. U. S. A. 90,8098-8102 15750
  5. Sanger, F., Nicklen, S., and Coulson, A. R. (1977) Proc. Natl. Acad. Sci. U. S. A. 23. Smith, D. B., and Johnson, K S. (1988) Gene (Amst.) 6 7 , 3 1 4 0

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Authors
Dong, L. M., Wilson, C., Wardell, M. R., Simmons, T., Mahley, R. W., Weisgraber, K. H., & Agard, D. A.
Affiliations
  • University of California, San Francisco (US)
  • Gladstone Institutes (US)
  • Howard Hughes Medical Institute (US)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1994-09
Volume
269
Issue
35
Pages
22358-22365
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/s0021-9258(17)31797-0
OpenAlex
W1559121591
Cited by
320
References
35
Citations by year
2026: 4 · 2025: 16 · 2024: 7 · 2023: 16 · 2022: 10 · 2021: 9 · 2020: 9 · 2019: 12 · 2018: 3 · 2017: 12 · 2016: 14 · 2015: 5 · 2014: 13 · 2013: 9 · 2012: 10
FWCI
10.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • Hertz Foundation
  • National Institutes of Health (2m01rr000083-41)
  • National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
  • National Center for Research Resources (RR 00083)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
apolipoprotein E, APOE ε4, apolipoprotein E3, lipoprotein binding, VLDL, high-density lipoprotein, salt bridges, C-terminal domain, N-terminal domain
MeSH terms
Animals, Apolipoproteins E, Arginine, Computer Graphics, Dogs, Escherichia coli, Glutathione Transferase, Humans, Lipoproteins, VLDL, Models, Molecular, Molecular Sequence Data, Rabbits, Recombinant Fusion Proteins, Mutagenesis, Site-Directed, Crystallography, X-Ray

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