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Cited by 100Protein Structure and DynamicsLipoproteins and Cardiovascular HealthEnzyme Structure and Function

Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein.

Wilson, Charles, Mau, Ted, Weisgraber, Karl H, Wardell, Mark R, Mahley, Robert W, Agard, David A·1994·Structure
DOI 10.1016/s0969-2126(00)00072-1
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Abstract

Background Apolipoprotein-E (apo-E), a 34kDa blood plasma protein, plays a key role in directing cholesterol transport via its interaction with the low density lipoprotein (LDL) receptor. The amino-terminal domain of apo-E forms an unusually elongated four-helix bundle arranged such that key basic residues involved in LDL receptor binding form a cluster at the end of one of the helices. A common apo-E variant, apo-E2, corresponding to the single-site substitution Arg158-->Cys, displays minimal LDL receptor binding and is associated with significant changes in plasma cholesterol levels and increased risk of coronary heart disease. Surprisingly, the site of mutation in this variant is physically well removed (> 12A) from the cluster of LDL receptor binding residues. Results We now report the refined crystal structure of the amino-terminal domain of apo-E2, at a nominal resolution of 3.0A. This structure reveals significant conformational changes relative to the wild-type protein that may account for reduced LDL receptor binding. Removal of the Arg158 side chain directly disrupts a pair of salt bridges, causing a compensatory reorganization of salt bridge partners that dramatically alters the charge surface presented by apo-E to its receptor. Conclusions It is proposed that the observed reorganization of surface salt bridges is responsible for the decreased receptor binding by apo-E2. This reorganization, essentially functioning as a mutationally induced electrostatic switch to…

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Crossref · 10.1016/s0969-2126(00)00072-1

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4 of 4 references verified0 citation errors · 0 not checkable

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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 [17]

  • The presence of cysteine at position 158 in ε2 disrupts the normal salt bridging required for the interaction of arginine at position 150 in the receptor binding region with the LDL receptor.

    “The presence of cysteine at position 158 in ε2 disrupts the normal salt bridging required for the interaction of arginine at position 150 in the receptor binding region with the LDL receptor17).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [17]

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Authors
Wilson, C., Mau, T., Weisgraber, K. H., Wardell, M. R., Mahley, R. W., & Agard, D. A.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of California, San Francisco (US)
ORCID
Venue
Structure
Publisher
Elsevier BV
Published
1994-08
Volume
2
Issue
8
Pages
713-718
ISSN
0969-2126 (ISSN-L)
DOI
10.1016/s0969-2126(00)00072-1
OpenAlex
W2112251329
Cited by
100
References
4
Citations by year
2026: 2 · 2025: 7 · 2024: 9 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 6 · 2019: 7 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 2 · 2012: 3
FWCI
0.88
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Structure (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
  • National Center for Research Resources (RR 1081, P41RR001081)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
apolipoprotein E, LDL receptor binding, salt bridges, N-terminal domain, crystal structure, conformational change, electrostatic interactions, cholesterol transport, coronary artery disease
MeSH terms
Apolipoproteins E, Computer Simulation, Crystallography, Humans, Models, Molecular, Mutation, Peptide Fragments, Protein Conformation, Receptors, LDL, Apolipoprotein E2

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