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Cited by 54Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid Membrane Structure and Behavior

Decoding of Lipoprotein−Receptor Interactions: Properties of Ligand Binding Modules Governing Interactions with Apolipoprotein E

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Guttman, Miklos, Prieto, J. Helena, Croy, Johnny E., Komives, Elizabeth A.·2010·Biochemistry
DOI 10.1021/bi9017208PMC PMC2821871
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Abstract

Clusters of complement-type ligand binding repeats in the LDL receptor family are thought to mediate the interactions between these receptors and their various ligands. Apolipoprotein E, a key ligand for cholesterol homeostasis, has been shown to interact with LDLR, LRP, and VLDLR, through these clusters. LDLR and VLDLR each contain a single ligand binding repeat cluster, whereas LRP contains three large clusters of ligand binding repeats, each with ligand binding functions. We show that within sLRP3 the three-repeat subcluster CR16-18 recapitulated ligand binding to the isolated receptor binding portion of ApoE (residues 130-149). Binding experiments with LA3-5 of LDLR and CR16-18 showed that a conserved W25/D30 pair appears to be critical for high-affinity binding to ApoE(130-149). The triple repeat LA3-5 showed the expected interaction with ApoE(1-191).DMPC, but surprisingly CR16-18 did not interact with this form of ApoE. To understand these differences in ApoE binding affinity, we introduced mutations of conserved residues from LA5 into CR18 and produced a CR16-18 variant capable of binding ApoE(1-191).DMPC. This change cannot fully be accounted for by the interaction with the proposed ApoE receptor binding region; therefore, we speculate that LA5 is recognizing a distinct epitope on ApoE that may only exist in the lipid-bound form. The combination of avidity effects with this distinct recognition process likely governs the ApoE-LDL receptor interaction.

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  • Amino acids 140-150 in the N-terminal domain are LDL receptor binding sites, and amino acids 244-272 in the C-terminal domain are binding sites for lipids.

    “Amino acids 140–150 in the N-terminal domain are low-density lipoprotein (LDL) receptor binding sites, and amino acids 244–272 in the C-terminal domain are binding sites for lipids [11].”

    From A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation (2024) · cites this paper as [11]

    The paper’s introductory passage identifies ApoE residues 140–150 in the N-terminal domain as a critical receptor-recognition site. It also says the C-terminal domain is involved in lipid binding, but the passages do not identify residues 244–272 as the lipid-binding site (page numbers are unavailable in our copy). (LLM, conf=0.87)

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Authors
Guttman, M., Prieto, J. H., Croy, J. E., & Komives, E. A.
Affiliations
  • Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0378
  • University of California San Diego (US)
Corresponding author
Komives, Elizabeth A.
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2010-01-19
Volume
49
Issue
6
Pages
1207-1216
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi9017208
PMC
PMC2821871
OpenAlex
W2124987022
Cited by
54
References
3
Citations by year
2026: 6 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 2 · 2018: 4 · 2017: 1 · 2015: 5 · 2014: 4 · 2013: 4
FWCI
2.03
Type
journal article
Language
en
Open access
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (AG025343, R01AG025343)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
apolipoprotein E, LDL receptor, low density lipoprotein receptor-related protein, VLDLR, ligand-receptor interactions, binding affinity, epitope recognition, avidity, cholesterol homeostasis, DMPC liposomes
MeSH terms
Amino Acid Sequence, Apolipoproteins E, Humans, Ligands, Molecular Sequence Data, Protein Binding, Receptors, LDL, Sequence Alignment, Protein Structure, Tertiary, Low Density Lipoprotein Receptor-Related Protein-1

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