Effects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE
Open accessAbstract
To understand the molecular basis for the differences in receptor-binding activity of the three common human apolipoprotein E (apoE) isoforms, we characterized the microenvironments of their LDL receptor (LDLR)-binding regions (residues 136;-150). When present in dimyristoyl phosphatidylcholine (DMPC) complexes, the 22-kDa amino-terminal fragments (residues 1;-191) of apoE3 and apoE4 bound to the LDLR with approximately 100-fold greater affinity than the 22-kDa fragment of apoE2. The pK(a) values of lysines (K) at positions 143 and 146 in the LDLR-binding region in DMPC-associated 22-kDa apoE fragments were 9.4 and 9.9 in apoE2, 9.5 and 9.2 in apoE3, and 9.9 and 9.4 in apoE4, respectively. The increased pK(a) of K146 in apoE2 relative to apoE3 arises from a reduction in the positive electrostatic potential in its microenvironment. This effect occurs because C158 in apoE2, unlike R158 in apoE3, rearranges the intrahelical salt bridges along the polar face of the amphipathic alpha-helix spanning the LDLR-binding region, reducing the effect of the R150 positive charge on K146 and concomitantly decreasing LDLR-binding affinity. The C112R mutation in apoE4 that differentiates it from apoE3 did not perturb the pK(a) of K146 significantly, but it increased the pK(a) of K143 in apoE4 by 0.4 pH unit. This change did not alter LDLR-binding affinity. Therefore, maintaining the appropriate positive charge at the C-terminal end of the receptor-binding region is particularly critical for effective interaction with acidic residues on the LDLR.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
APOE2 exhibits a lower LDLR binding capacity than APOE4.
“Biochemical studies have also identified isoform‐specific differences in LDLR binding, with APOE2 exhibiting a lower binding capacity than APOE4 does.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [68]
ApoE2 has lower receptor binding affinity than apoE3 and apoE4.
“ApoE2 has lower receptor binding affinity than apoE3 and apoE4 [ 41].”
From ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age (2006) · cites this paper as [41]
The greater binding of apoE4 to HS and DS results from enhanced electrostatic interaction through the N-terminal domain.
“perhaps resulting from enhanced electrostatic interaction through the N-terminal domain.”
From Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study (2008) · cites this paper as [49]
The increased binding of full-length apoE4 to GAG comes from enhanced electrostatic interaction through the N-terminal binding site.
“This suggests that the increased binding of full-length apoE4 to GAG comes from enhanced electrostatic interaction through the N-terminal binding site (49).”
From Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study (2008) · cites this paper as [49]
Cites
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028 · see citing works
Marion, D., & Wüthrich, K. (1983) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(83)91093-8 · Cited by 3,160 · see citing works
RASMOL: biomolecular graphics for all
Sayle, R. A. (1995) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)89080-5 · Cited by 2,587 · see citing works
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Self-citationMahley, R. W., & Ji, Z.-S. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33334-4 · Cited by 693 · see citing works
Three-Dimensional Structure of the LDL Receptor-Binding Domain of Human Apolipoprotein E
Wilson, C., Wardell, M. R., Weisgraber, K. H., Mahley, R. W., & Agard, D. A. (1991) · Science · doi:10.1126/science.2063194 · Cited by 678 · see citing works
Self-citationWeisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34954-8 · Cited by 673 · see citing works
Self-citationMahley, R. W., Huang, Y., & Rall, S. C. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32417-2 · Cited by 447 · see citing works
Mahley, R. W., & Huang, Y. (1999) · Current Opinion in Lipidology · doi:10.1097/00041433-199906000-00003 · Cited by 388 · see citing works
Human apolipoprotein E: the Alzheimer's disease connection
Weisgraber, K. H., & Mahley, R. W. (1996) · The FASEB Journal · doi:10.1096/fasebj.10.13.8940294 · Cited by 327 · see citing works
Self-citationDong, 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 · Cited by 320 · see citing works
Self-citationWeisgraber, K. H. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42621-5 · Cited by 304 · see citing works
Self-citationInnerarity, T. L., Pitas, R. E., & Mahley, R. W. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)50713-4 · Cited by 300 · see citing works
The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments.
Innerarity, T. L., Friedlander, E. J., Rall, S. C., Weisgraber, K. H., & Mahley, R. W. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44180-9 · Cited by 276 · see citing works
Self-citationEichner, J. E., Kuller, L. H., Orchard, T. J., Grandits, G. A., McCallum, L. M., Ferrell, R. E., & Neaton, J. D. (1993) · The American Journal of Cardiology · doi:10.1016/0002-9149(93)90732-r · Cited by 247 · see citing works
Lalazar (1989) · doi:10.1016/s0021-9258(18)81806-3 · Cited by 238 · see citing works
Luc, G., Bard, J., Arveiler, D., Evans, A., Cambou, J., Bingham, A., Amouyel, P., Schaffer, P., Ruidavets, J., & Cambien, F. (1994) · Arteriosclerosis and Thrombosis A Journal of Vascular Biology · doi:10.1161/01.atv.14.9.1412 · Cited by 215 · see citing works
LeMaster, D. M., & Richards, F. M. (1985) · Biochemistry · doi:10.1021/bi00346a036 · Cited by 213 · see citing works
[50] Protein labeling by reductive alkylation
Jentoft, N., & Dearborn, D. G. (1983) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(83)91052-2 · Cited by 208 · see citing works
Innerarity, T. L., Weisgraber, K. H., Arnold, K. S., Rall, S. C., & Mahley, R. W. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)39866-6 · Cited by 179 · see citing works
Self-citationApolipoprotein E phenotypes in patients with myocardial infarction
Utermann, G., Hardewig, A., & Zimmer, F. (1984) · Human Genetics · doi:10.1007/bf00286509 · Cited by 150 · see citing works
Christl, M., & Roberts, J. D. (1972) · Journal of the American Chemical Society · doi:10.1021/ja00768a026 · Cited by 134 · see citing works
Sparks, D. L., Phillips, M. C., & Lund‐Katz, S. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)35685-0 · Cited by 133 · see citing works
Self-citationSokoloff, L., & Rothblat, G. H. (1974) · Experimental Biology and Medicine · doi:10.3181/00379727-146-38267 · Cited by 132 · see citing works
Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia
Dong, L., Parkin, S., Trakhanov, S. D., Rupp, B., Simmons, T., Arnold, K. S., Newhouse, Y. M., Innerarity, T. L., & Weisgraber, K. H. (1996) · Nature Structural & Molecular Biology · doi:10.1038/nsb0896-718 · Cited by 129 · see citing works
Self-citationRoberts, G. C. K. (2012) · Springer eBooks · doi:10.1007/978-3-642-16712-6_100050 · Cited by 118 · see citing works
Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein.
Wilson, C., Mau, T., Weisgraber, K. H., Wardell, M. R., Mahley, R. W., & Agard, D. A. (1994) · Structure · doi:10.1016/s0969-2126(00)00072-1 · Cited by 100 · see citing works
Self-citation友也, 田., 定也, 美., & 貴史, 伊. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003508200 · Cited by 95 · see citing works
Lipid binding-induced conformational changes in the N-terminal domain of human apolipoprotein E
Fisher, C. A., & Ryan, R. O. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33343-5 · Cited by 95 · see citing works
Functional Characterization of Apolipoprotein E Isoforms Overexpressed in Escherichia coli
Morrow, J. A., Arnold, K. S., & Weisgraber, K. H. (1999) · Protein Expression and Purification · doi:10.1006/prep.1999.1069 · Cited by 94 · see citing works
Self-citationLund‐Katz, S., Ibdah, J. A., Letizia, J. Y., Thomas, M. T., & Phillips, M. C. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68319-x · Cited by 77 · see citing works
Self-citationZaiou, M., Arnold, K. S., Newhouse, Y. M., Innerarity, T. L., Weisgraber, K. H., Segall, M. L., Phillips, M. C., & Lund‐Katz, S. (2000) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32014-9 · Cited by 77 · see citing works
Self-citationSolution Structure of the Sixth LDL-A Module of the LDL Receptor,
North, C. L., & Blacklow, S. C. (2000) · Biochemistry · doi:10.1021/bi992087a · Cited by 67 · see citing works
Effects of Lipid Interaction on the Lysine Microenvironments in Apolipoprotein E
Lund‐Katz, S., Zaiou, M., Wehrli, S. L., Dhanasekaran, P., Baldwin, F., Weisgraber, K. H., & Phillips, M. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005265200 · Cited by 54 · see citing works
Self-citationSegelke, B. W., Forstner, M., Knapp, M., Trakhanov, S. D., Parkin, S., Newhouse, Y. M., Bellamy, H. D., Weisgraber, K. H., & Rupp, B. (2000) · Protein Science · doi:10.1110/ps.9.5.886 · Cited by 47 · see citing works
Self-citationConformation of apolipoprotein E in lipoproteins.
Lund‐Katz, S., Weisgraber, K. H., Mahley, R. W., & Phillips, M. C. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)49418-0 · Cited by 40 · see citing works
Self-citationDong, L., Innerarity, T. L., Arnold, K. S., Newhouse, Y. M., & Weisgraber, K. H. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32541-4 · Cited by 26 · see citing works
Self-citationScapin, G., Sacchettini, J. C., Dessen, A., et al. (1993) · Journal of Molecular Biology · doi:10.1006/jmbi.1993.1244 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age
Mooijaart, S. P., Berbée, J. F. P., van Heemst, D., Havekes, L. M., de Craen, A. J. M., Slagboom, P. E., Rensen, P. C. N., & Westendorp, R. G. J. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030176 · Cited by 129 · see citing works
Lipid Binding-induced Conformational Change in Human Apolipoprotein E
Saito, H., Dhanasekaran, P., Baldwin, F., Weisgraber, K. H., Lund-Katz, S., & Phillips, M. C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106337200 · Cited by 113 · see citing works
Self-citationTwo-step Mechanism of Binding of Apolipoprotein E to Heparin
Futamura, M., Dhanasekaran, P., Handa, T., Phillips, M. C., Lund-Katz, S., & Saito, H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411719200 · Cited by 91 · see citing works
Self-citationCharacterization of the Heparin Binding Sites in Human Apolipoprotein E
Saito, H., Dhanasekaran, P., Nguyen, D., Baldwin, F., Weisgraber, K. H., Wehrli, S., Phillips, M. C., & Lund-Katz, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213207200 · Cited by 90 · see citing works
Self-citationYamauchi, Y., Deguchi, N., Takagi, C., Tanaka, M., Dhanasekaran, P., Nakano, M., Handa, T., Phillips, M. C., Lund-Katz, S., & Saito, H. (2008) · Biochemistry · doi:10.1021/bi8003999 · Cited by 53 · see citing works
Self-citationStructural Analysis of Lipoprotein E Particles
Schneeweis, L. A., Koppaka, V., Lund-Katz, S., Phillips, M. C., & Axelsen, P. H. (2005) · Biochemistry · doi:10.1021/bi050872j · Cited by 39 · see citing works
Self-citationClément-Collin, V., Barbier, A., Dergunov, A. D., Visvikis, A., Siest, G., Desmadril, M., Takahashi, M., & Aggerbeck, L. P. (2006) · Biophysical Chemistry · doi:10.1016/j.bpc.2005.07.009 · Cited by 32 · see citing works
Karahan, H., Hartigan, K., Al‐Amin, M. M., John, S. K., McCord, B., Wijeratne, H. R. S., Acri, D. J., Smith, D. C., Dabin, L. C., Cordero, H. M. R., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70949 · Cited by 2 · see citing works
- Authors
- Lund-Katz, S., Wehrli, S., Zaiou, M., Newhouse, Y., Weisgraber, K. H., & Phillips, M. C.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Hahnemann University Hospital (US)
- University of California, San Francisco (US)
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2001-06
- Volume
- 42
- Issue
- 6
- Pages
- 894-901
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2101105961
- Cited by
- 40
- References
- 39
- Citations by year
- 2025: 3 · 2023: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2015: 3 · 2013: 2 · 2012: 1
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Heart, Lung, and Blood Institute (HL-41633, P01HL041633, R01HL056083, HL-56083)
- National Center for Research Resources (RR 01614, P41RR001614)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- 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, APOE isoforms, LDL receptor binding, polymorphism, APOE2, APOE3, APOE ε4, microenvironment, electrostatic potential, amphipathic helix, dimyristoylphosphatidylcholine, receptor binding affinity
- MeSH terms
- Amino Acids, Apolipoproteins E, Binding Sites, Cysteamine, Dimyristoylphosphatidylcholine, Ferricyanides, Humans, Hydrogen-Ion Concentration, Lysine, Models, Molecular, Mutation, Magnetic Resonance Spectroscopy, Polymorphism, Genetic, Protein Binding, Receptors, LDL, Protein Structure, Tertiary, Protein Isoforms
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
