Characterization of the Heparin Binding Sites in Human Apolipoprotein E
Open accessAbstract
Apolipoprotein (apo) E mediates lipoprotein remnant clearance via interaction with cell-surface heparan sulfate proteoglycans. Both the 22-kDa N-terminal domain and 10-kDa C-terminal domain of apoE contain a heparin binding site; the N-terminal site overlaps with the low density lipoprotein receptor binding region and the C-terminal site is undefined. To understand the molecular details of the apoE-heparin interaction, we defined the microenvironments of all 12 lysine residues in intact apoE3 and examined their relative contributions to heparin binding. Nuclear magnetic resonance measurements showed that, in apoE3-dimyristoyl phosphatidylcholine discs, Lys-143 and -146 in the N-terminal domain and Lys-233 in the C-terminal domain have unusually low pK(a) values, indicating high positive electrostatic potential around these residues. Binding experiments using heparin-Sepharose gel demonstrated that the lipid-free 10-kDa fragment interacted strongly with heparin and a point mutation K233Q largely abolished the binding, indicating that Lys-233 is involved in heparin binding and that an unusually basic lysine microenvironment is critical for the interaction with heparin. With lipidated apoE3, it is confirmed that the Lys-233 site is completely masked and the N-terminal site mediates heparin binding. In addition, mutations of the two heparin binding sites in intact apoE3 demonstrated the dominant role of the N-terminal site in the heparin binding of apoE even in the lipid-free state. These results suggest that apoE interacts predominately with cell-surface heparan sulfate proteoglycans through the N-terminal binding site. However, Lys-233 may be involved in the binding of apoE to certain cell-surface sites, such as the protein core of biglycan.
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Lipid-bound apoE3[K146E] has less than 10% binding capacity to the LDL receptor and HSPG compared with apoE3.
“Lipid-bound apoE3[K146E] had less than 10% binding capacity to the LDL receptor and HSPG compared with apoE3 [34], [35], [36].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [36]
An HSPG and LDLR binding site in the APOE sequence is conserved in mice (AA136-150), including arginine 136, which is replaced by serine in the Christchurch (Ch) variant.
“Notably, an HSPG and LDLR binding site in the APOE sequence is conserved in mice (blue boxed area, AA136-150), including arginine 136, which is replaced by serine in the Christchurch (Ch) variant [12, 39].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [39]
mAPOE and hAPOE have a conserved LDLR and HSPG binding motif between AA136 to 150 (human numbering), which includes R136S Christchurch variant.
“However, mAPOE and hAPOE have a conserved LDLR and HSPG binding motif between AA136 to 150 (human numbering) [11, 12, 39], which includes the R136S Christchurch variant.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [39]
The C-terminal domain of apoE contains a heparin binding site involving basic residues around lysine 233.
“whereas the C-terminal site involves basic residues around lysine 233 (27).”
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 [27]
Although both heparin binding sites are functional in separated fragments, only the N-terminal site is available for interaction in both lipid-free and lipidated states of intact apoE.
“Although both sites are functional in the separated fragments, only the N-terminal site is available for interaction in both the lipid-free and lipidated states of the intact apoE molecule (27, 28).”
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 [27]
The C-terminal domain contributes to the high-affinity binding of apoE to GAG through an oligomerization effect.
“Rather, the C-terminal domain appears to contribute to the high-affinity binding of apoE to GAG through an oligomerization effect (27).”
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 [27]
The C-terminal site (basic residues around lysine 233) is not available for the interaction of full-length apoE with GAG.
“In contrast to the dominant role of the N-terminal site in apoE to GAG binding, the C-terminal site (basic residues around lysine 233) is not available for the interaction of full-length apoE with GAG (Fig. 4) (27, 28).”
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 [27]
Cooperative binding through multiple copies of the heparin binding sites of apoE molecules is important for the high affinity binding to GAG.
“These results suggest that the cooperative binding through multiple copies of the heparin binding sites of apoE molecules is important for the high affinity binding to GAG (27).”
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 [27]
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
Phosphorus Assay in Column Chromatography
Bartlett, G. R. (1959) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)70226-3 · Cited by 12,802 · 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
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836 · see citing works
Segrest, J., Jones, M., Loof, H. D., Brouillette, C. G., Venkatachalapathi, Y. V., & Anantharamaiah, G. M. (1992) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)41536-6 · Cited by 868 · 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-citationHepatic uptake of chylomicron remnants
Cooper, A. D. (1997) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)34932-4 · Cited by 499 · see citing works
Huang, Y., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A., & Mahley, R. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151254698 · Cited by 392 · see citing works
Holtzman, D. M., Pitas, R. E., Kilbridge, J., Nathan, B., Mahley, R. W., Bu, G., & Schwartz, A. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.21.9480 · Cited by 349 · 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-citationThe Amphipathic α Helix: A Multifunctional Structural Motif in Plasma Apolipoproteins
Segrest, J. P., Garber, D. W., Brouillette, C. G., Harvey, S. C., & Anantharamaiah, G. M. (1994) · Advances in protein chemistry · doi:10.1016/s0065-3233(08)60643-9 · Cited by 310 · 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-citationComparison of Apolipoprotein and Proteoglycan Deposits in Human Coronary Atherosclerotic Plaques
O’Brien, K. D., Olin, K. L., Alpers, C. E., Chiu, W. S., Ferguson, M. S., Hudkins, K. L., Wight, T. N., & Chait, A. (1998) · Circulation · doi:10.1161/01.cir.98.6.519 · Cited by 271 · see citing works
Human apolipoprotein E. Determination of the heparin binding sites of apolipoprotein E3.
Weisgraber, K. H., Rall, S. C., Mahley, R. W., Milne, R. W., Marcel, Y. L., & Sparrow, J. T. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)35898-2 · Cited by 240 · see citing works
Self-citationJi, Z. S., Brecht, W. J., Miranda, R. D., Hussain, M. M., Innerarity, T. L., & Mahley, R. W. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82186-x · Cited by 240 · see citing works
Aggerbeck, L. P., Wetterau, J. R., Weisgraber, K. H., Wu, C. S., & Lindgren, F. T. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68779-4 · Cited by 229 · see citing works
Self-citationJi, Z. S., Fazio, S., Lee, Y. L., & Mahley, R. W. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42009-6 · Cited by 209 · see citing works
Westerlund, J. A., & Weisgraber, K. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82318-3 · Cited by 164 · see citing works
Self-citationJi, Z. S., Fazio, S., & Mahley, R. W. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36849-7 · Cited by 138 · see citing works
Ji, Z.-S., Pitas, R. E., & Mahley, R. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13452 · Cited by 134 · see citing works
Cardin, A. D., Hirose, N., Blankenship, D. T., Jackson, R. L., Harmony, J. A. K., Sparrow, D. A., & Sparrow, J. T. (1986) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(86)80489-2 · Cited by 114 · 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-citationNew Insights into the Heparan Sulfate Proteoglycan-binding Activity of Apolipoprotein E
Libeu, C. P., Lund-Katz, S., Phillips, M. C., Wehrli, S., Hernáiz, M. J., Capila, I., Linhardt, R. J., Raffaı̈, R. L., Newhouse, Y. M., Zhou, F., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104746200 · Cited by 113 · see citing works
Self-citationDesign of Peptides with High Affinities for Heparin and Endothelial Cell Proteoglycans
Verrecchio, A., Germann, M. W., Schick, B. P., Kung, B., Twardowski, T., & San Antonio, J. D. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.11.7701 · Cited by 102 · see citing works
Interaction of the N-Terminal Domain of Apolipoprotein E4 with Heparin
Dong, J., Peters-Libeu, C. A., Weisgraber, K. H., Segelke, B. W., Rupp, B., Capila, I., Hernáiz, M. J., LeBrun, L. A., & Linhardt, R. J. (2001) · Biochemistry · doi:10.1021/bi002417n · Cited by 99 · 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-citationFisher, C. A., Narayanaswami, V., & Ryan, R. O. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002643200 · Cited by 78 · see citing works
Lund‐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-citationCell Surface Proteoglycans Modulate Net Synthesis and Secretion of Macrophage Apolipoprotein E
Lucas, M., & Mazzone, T. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.23.13454 · Cited by 63 · see citing works
[28] Molecular design and modeling of protein—heparin interactions
Cardin, A. D., Demeter, D. A., Weintraub, H. J. R., & Jackson, R. L. (1991) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(91)03030-k · Cited by 60 · see citing works
Swertfeger, D. K., & Hui, D. Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102357200 · Cited by 59 · see citing works
Apolipoprotein E Carboxyl-terminal Fragments Are Complexed to Amyloids A and L
Castaño, E. M., Prelli, F. C., Pras, M., & Frangione, B. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.29.17610 · Cited by 59 · 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-citationLipid Association-induced N- and C-terminal Domain Reorganization in Human Apolipoprotein E3
Narayanaswami, V., Szeto, S. S. W., & Ryan, R. O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102953200 · Cited by 53 · see citing works
Mann, W. A., Meyer, N., Weber, W. T., Meyer, S., Greten, H., & Beisiegel†, U. (1995) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39885-0 · Cited by 47 · see citing works
Biglycan, a Vascular Proteoglycan, Binds Differently to HDL 2 and HDL 3
Olin, K. L., Potter‐Perigo, S., Barrett, P. H. R., Wight, T. N., & Chait, A. (2001) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.21.1.129 · Cited by 45 · see citing works
Only multimers of a synthetic peptide of human apolipoprotein E are biologically active
Dyer, C. A., Smith, R. S., & Curtiss, L. K. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98578-9 · Cited by 41 · see citing works
Conformation 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-citationEffects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE
Lund-Katz, S., Wehrli, S., Zaiou, M., Newhouse, Y., Weisgraber, K. H., & Phillips, M. C. (2001) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)31612-6 · Cited by 40 · see citing works
Self-citationFunahashi, T., Yokoyama, S., & Yamamoto, A. (1989) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a122708 · Cited by 33 · see citing works
Lin, C.-Y., Huang, Z., & Mazzone, T. (2001) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)31603-5 · Cited by 32 · see citing works
The HepG2 Extracellular Matrix Contains Separate Heparinase- and Lipid-releasable Pools of ApoE
Burgess, J. W., Gould, D. R., & Marcel, Y. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.10.5645 · Cited by 30 · see citing works
Aizawa, Y., Fukatsu, R., Takamaru, Y., Tsuzuki, K., Chiba, H., Kobayashi, K., Fujii, N., & Takahata, N. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00640-9 · Cited by 29 · see citing works
Shuvaev, V. V., Laffont, I., & Siest, G. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01285-5 · Cited by 27 · see citing works
Heparin specifically inhibits binding of apolipoprotein E to amyloid β-peptide
Shuvaev, V. V., & Siest, G. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)00764-3 · Cited by 19 · see citing works
Klezovitch, O., Formato, M., Cherchi, G. M., Weisgraber, K. H., & Scanu, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m909644199 · Cited by 17 · see citing works
Self-citationDong, J., Balestra, M. E., Newhouse, Y. M., & Weisgraber, K. H. (2000) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)31971-4 · Cited by 11 · see citing works
Self-citationStructural Properties of the Heparin-Binding Domains of Human Apolipoprotein E
Cardin, A. D., & Jackson, R. L. (1988) · Advances in experimental medicine and biology · doi:10.1007/978-1-4613-0733-4_19 · Cited by 6 · see citing works
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Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
Apolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease
Zhao, N., Liu, C.-C., Qiao, W., & Bu, G. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.03.003 · Cited by 370 · see citing works
APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
Li, Z., Shue, F., Zhao, N., Shinohara, M., & Bu, G. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00413-4 · Cited by 306 · see citing works
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Chen, J., Li, Q., & Wang, J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106420108 · Cited by 283 · see citing works
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
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Ramasamy, I. (2013) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2013-0358 · Cited by 234 · see citing works
Owen, D. M., Huang, H., Ye, J., & Gale, M. (2009) · Virology · doi:10.1016/j.virol.2009.08.037 · Cited by 234 · see citing works
Saito, H., Lund‐Katz, S., & Phillips, M. C. (2004) · Progress in Lipid Research · doi:10.1016/j.plipres.2004.05.002 · Cited by 216 · see citing works
Self-citationZeisel, M. B., Felmlee, D. J., & Baumert, T. F. (2013) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-27340-7_4 · Cited by 181 · see citing works
Kim, K., Ryu, J., Koh, M.-Y., Yun, S., Kim, S., Park, J. P., Jung, C., Lee, M. S., Seo, H., Kim, J. H., et al. (2021) · Science Advances · doi:10.1126/sciadv.abc9992 · Cited by 140 · see citing works
Morita, S. (2015) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b15-00716 · Cited by 156 · see citing works
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Choy, N., Raussens, V., & Narayanaswami, V. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.09.059 · Cited by 131 · see citing works
<i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9375 · Cited by 108 · see citing works
Jendresen, C., Årskog, V., Daws, M. R., & Nilsson, L. N. G. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0835-4 · Cited by 94 · see citing works
The Receptor‐Binding Region of Human Apolipoprotein E Has Direct Anti‐Infective Activity
Dobson, C. B., Sales, S. D., Hoggard, P. G., Wozniak, M. A., & Crutcher, K. A. (2006) · The Journal of Infectious Diseases · doi:10.1086/499280 · Cited by 92 · see citing works
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Raulin, A.-C., Martens, Y. A., & Bu, G. (2022) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-032620-104801 · Cited by 89 · see citing works
Nguyen, D., Dhanasekaran, P., Nickel, M., Nakatani, R., Saito, H., Phillips, M. C., & Lund-Katz, S. (2010) · Biochemistry · doi:10.1021/bi1017655 · Cited by 89 · see citing works
Self-citationEffects of Polymorphism on the Lipid Interaction of Human Apolipoprotein E
Saito, H., Dhanasekaran, P., Baldwin, F., Weisgraber, K. H., Phillips, M. C., & Lund-Katz, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304814200 · Cited by 89 · see citing works
Self-citationLeroy, A., Landrieu, I., Huvent, I., Legrand, D., Codeville, B., Wieruszeski, J.-M., & Lippens, G. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.149419 · Cited by 86 · see citing works
Snow, A. D., Cummings, J. A., & Lake, T. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.710683 · Cited by 84 · see citing works
Cathepsin D-mediated proteolysis of apolipoprotein E: Possible role in Alzheimer’s disease
Zhou, W., Scott, S. A., Shelton, S. B., & Crutcher, K. A. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.08.019 · Cited by 82 · see citing works
Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans
Gonzales, J. C., Gordts, P. L. S. M., Foley, E. M., & Esko, J. D. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67398 · Cited by 79 · see citing works
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Pattipeiluhu, R., Crielaard, S., Klein-Schiphorst, I., Florea, B. I., Kros, A., & Campbell, F. (2020) · ACS Central Science · doi:10.1021/acscentsci.9b01222 · Cited by 74 · see citing works
Fu, Y., Zhao, J., Atagi, Y., Nielsen, H. M., Liu, C., Zheng, H., Shinohara, M., Kanekiyo, T., & Bu, G. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0099-y · Cited by 71 · see citing works
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Narayanaswami, V., Kiss, R. S., & Weers, P. M. M. (2009) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2009.09.009 · Cited by 67 · see citing works
Yamauchi, 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-citationNoborn, F., Ancsin, J. B., Ubhayasekera, W., Kisilevsky, R., & Li, J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.363895 · Cited by 55 · see citing works
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Heparan sulfate proteoglycans and triglyceride-rich lipoprotein metabolism
Bishop, J. R., Stanford, K. I., & Esko, J. D. (2008) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3282feec2d · Cited by 52 · see citing works
Luo, J., Maréchal, J., Wärmländer, S. K. T. S., Gräslund, A., & Perálvarez‐Marín, A. (2010) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000663 · Cited by 51 · see citing works
Canchola, A., Li, K., Chen, K., Borboa-Pimentel, A., Chou, C., Rama, R. D., Chen, C., Chen, X., Strobel, M. J., Riviere, J. E., et al. (2025) · ACS Nano · doi:10.1021/acsnano.5c08608 · Cited by 49 · see citing works
Alzheimer's Disease: Another Target for Heparin Therapy
Bergamaschini, L. C., Rossi, E., Vergani, C., & Simoni, M. G. D. (2009) · The Scientific World JOURNAL · doi:10.1100/tsw.2009.100 · Cited by 46 · see citing works
Tamamizu‐Kato, S., Wong, J. Y., Jairam, V., Uchida, K., Raussens, V., Kato, H., Ruysschaert, J., & Narayanaswami, V. (2007) · Biochemistry · doi:10.1021/bi700289k · Cited by 46 · see citing works
McMillan, I. O., Li, J., & Wang, L. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00247.2022 · Cited by 42 · see citing works
Multi-functional role of apolipoprotein E in neurodegenerative diseases
Islam, S., Noorani, A. A., Sun, Y., Michikawa, M., & Zou, K. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1535280 · Cited by 41 · see citing works
High‐affinity multivalent interactions between apolipoprotein E and the oligomers of amyloid‐β
Ghosh, S., Sil, T. B., Dolai, S., & Garai, K. (2019) · FEBS Journal · doi:10.1111/febs.14988 · Cited by 40 · see citing works
Apolipoprotein E-mediated regulation of selenoprotein P transportation via exosomes
Jin, Y., Chung, Y. W., Jung, M. K., Lee, J. H., Ko, K. Y., Jang, J. K., Ham, M., Kang, H., Pack, C. G., Mihara, H., et al. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03287-y · Cited by 39 · see citing works
Generation of a Recombinant Apolipoprotein E Variant with Improved Biological Functions
Kypreos, K. E., van Dijk, K. W., Havekes, L. M., & Zannis, V. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m413458200 · Cited by 37 · see citing works
The role of full-length apoE in clearance of Gram-negative bacteria and their endotoxins
Petruk, G., Elvén, M., Hartman, E., Davoudi, M., Schmidtchen, A., Puthia, M., & Petrlová, J. (2021) · Journal of Lipid Research · doi:10.1016/j.jlr.2021.100086 · Cited by 33 · see citing works
Chuang, S. T., Cruz, S., & Narayanaswami, V. (2020) · Nanomaterials · doi:10.3390/nano10050906 · Cited by 33 · see citing works
Effective Treatment of Ocular HSK with a Human Apolipoprotein E Mimetic Peptide in a Mouse Eye Model
Bhattacharjee, P. S., Neumann, D. M., Foster, T. P., Clément, C., Singh, G., Thompson, H. W., Kaufman, H. E., & Hill, J. M. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-2077 · Cited by 32 · see citing works
Sheng, Z., Prorok, M., Brown, B., & Castellino, F. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.05.016 · Cited by 32 · see citing works
Hueging, K., Weller, R., Doepke, M., Vièyres, G., Tödt, D., Wölk, B., Vondran, F. W. R., Geffers, R., Lauber, C., Kaderali, L., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134529 · Cited by 31 · see citing works
Bhattacharjee, P. S., Huq, T. S., Mandal, T. K., Graves, R. A., Muniruzzaman, S., Clément, C., McFerrin, H. E., & Hill, J. M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015905 · Cited by 31 · see citing works
Heparin-enriched plasma proteome is significantly altered in Alzheimer’s disease
Guo, Q. J., Ping, L., Dammer, E. B., Duong, D. M., Yin, L., Xu, K., Shantaraman, A., Fox, E. J., Golde, T. E., Johnson, E. C. B., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00757-1 · Cited by 37 · see citing works
Apo<scp>E</scp>: The role of conserved residues in defining function
Frieden, C. (2015) · Protein Science · doi:10.1002/pro.2597 · Cited by 29 · see citing works
Tran, K. M., Kwang, N. E., Butler, C. A., Gomez-Arboledas, A., Kawauchi, S., Mar, C., Chao, D., Barahona, R. A., Da Cunha, C., Tsourmas, K. I., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00793-x · Cited by 28 · see citing works
Antibacterial and Anti-Inflammatory Effects of Apolipoprotein E
Puthia, M., Marzinek, J. K., Petruk, G., Ertürk, G., Bond, P. J., & Petrlová, J. (2022) · Biomedicines · doi:10.3390/biomedicines10061430 · Cited by 27 · see citing works
Bång-Rudenstam, A., Cerezo-Magaña, M., & Belting, M. (2019) · Cancer and Metastasis Reviews · doi:10.1007/s10555-019-09786-5 · Cited by 25 · see citing works
Kim, W. S., Elliott, D. A., Kockx, M., Kritharides, L., Rye, K., Jans, D. A., & Garner, B. (2008) · Biochemical Journal · doi:10.1042/bj20071261 · Cited by 25 · see citing works
Georgiadou, D., Chroni, A., Vezeridis, A., Zannis, V. I., & Stratikos, E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027037 · Cited by 24 · see citing works
Muñoz, S. S., Li, H., Ruberu, K. R., Chu, Q., Saghatelian, A., Ooi, L., & Garner, B. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001278 · Cited by 24 · see citing works
ApoE: In Vitro Studies of a Small Molecule Effector
Mondal, T., Wang, H., DeKoster, G. T., Baban, B. A., Gross, M. L., & Frieden, C. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00324 · Cited by 23 · see citing works
Ohgita, T., Takechi‐Haraya, Y., Nadai, R., Kotani, M., Tamura, Y., Karin, N., Nishitsuji, K., Uchimura, K., Hasegawa, K., Sakai‐Kato, K., et al. (2018) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2018.12.010 · Cited by 23 · see citing works
Self-citationApolipoprotein E Recognizes Alzheimer's Disease Associated 3‐O Sulfation of Heparan Sulfate
Mah, D., Zhu, Y., Su, G., Zhao, J., Canning, A., Gibson, J. M., Song, X., Stancanelli, E., Xu, Y., Zhang, F., et al. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202212636 · Cited by 23 · see citing works
Chen, G., Wang, M., Zhang, Z., Hong, D. K., Ahn, E. H., Liu, X., Kang, S. S., & Ye, K. (2025) · Neuron · doi:10.1016/j.neuron.2024.12.015 · Cited by 21 · see citing works
Exploring the glycosaminoglycan–protein interaction network by glycan‐mediated pull‐down proteomics
Gesslbauer, B., Derler, R., Handwerker, C., Seles, E., & Kungl, A. J. (2016) · Electrophoresis · doi:10.1002/elps.201600043 · Cited by 20 · see citing works
Human apolipoprotein E glycosylation and sialylation: from structure to function
Moon, H.-J., Luo, Y., Chugh, D., & Zhao, L. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1399965 · Cited by 18 · see citing works
Chang, C., Wang, G., Kuo, C., Hsieh, J.-Y., Lee, A.-S., Chang, C., Wang, C., Shen, M., Huang, C., Sawamura, T., et al. (2016) · Medicine · doi:10.1097/md.0000000000002265 · Cited by 17 · see citing works
Structure–function properties of the apoE-dependent COX-2 pathway in vascular smooth muscle cells
Ali, K., Lund‐Katz, S., Lawson, J. A., Phillips, M. C., & Rader, D. J. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.03.038 · Cited by 17 · see citing works
Self-citationIn Vitro Interaction of Melanoma-Derived Extracellular Vesicles with Collagen
Palmulli, R., Bresteau, E., Raposo, G., Montagnac, G., & van Niel, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043703 · Cited by 16 · see citing works
Morita, S., Sakurai, A., Nakano, M., Kitagawa, S., & Handa, T. (2010) · Lipids · doi:10.1007/s11745-010-3498-9 · Cited by 15 · see citing works
Lipponen, K., Tähkä, S. M., Samuelsson, J., Jauhiainen, M., Metso, J., Cilpa-Karhu, G., Fornstedt, T., Kostiainen, M. A., & Riekkola, M. (2014) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-014-7821-9 · Cited by 12 · see citing works
Guha, M., & Gursky, O. (2011) · Journal of Lipids · doi:10.1155/2011/493720 · Cited by 12 · see citing works
Guo, Q. J., Ping, L., Dammer, E. B., Duong, D. M., Yin, L., Xu, K., Shantaraman, A., Fox, E. J., Johnson, E. C. B., Roberts, B. R., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.06.565824 · Cited by 11 · see citing works
Bugs, M. R., Bortoleto, R. K., & Cornélio, M. L. (2005) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2005.08.003 · Cited by 10 · see citing works
Recruitment of apolipoprotein E facilitates Herpes simplex virus 1 attachment and release
Liu, L., Bano, F., Conca, D. V., Thorsteinsson, K., Jayaweera, S. W., Avinens, D., Pace, H. P., Lövheim, H., Olofsson, A., & Bally, M. (2025) · npj Viruses · doi:10.1038/s44298-025-00099-9 · Cited by 8 · see citing works
Peptidomic analysis of endogenous and bacterial protease activity in human plasma and wound fluids
Cai, J. C., Nielsen, M. W., Kalogeropoulos, K., Keller, U. A. D., & van der Plas, M. J. A. (2024) · iScience · doi:10.1016/j.isci.2024.109005 · Cited by 7 · see citing works
ApoE3 Christchurch and tau interaction as a protective mechanism against Alzheimer's disease
Perez‐Corredor, P., Arevalo‐Alquichire, S., Mazzarino, R. C., O'Hare, M., Muriel‐Torres, A. F., Vacano, G. N., Vanderleest, T. E., Miller, W. P., Pineda‐Lopez, L., Patel, S., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70396 · Cited by 7 · see citing works
Aguilar-Pineda, J. A., Paco-Coralla, S. G., Febres-Molina, C., Gamero-Begazo, P. L., Shrivastava, P., Vera-López, K. J., Dávila-Del-Carpio, G., López-Casaperalta, P., Gómez, B., & Cardenas, C. L. L. (2022) · Biomolecules · doi:10.3390/biom12040499 · Cited by 7 · see citing works
Apolipoprotein-mimetic Peptides: Current and Future Prospectives
Pande, A. H., Nankar, S. A., Ahmed, S., & Sharma, S. S. (2022) · Current Protein and Peptide Science · doi:10.2174/1389203723666221003122624 · Cited by 6 · see citing works
Ikeda, T., Shinohata, R., Murakami, M., Hina, K., Kamikawa, S., Hirohata, S., Kusachi, S., Tamura, A., & Usui, S. (2016) · Clinica Chimica Acta · doi:10.1016/j.cca.2016.12.016 · Cited by 6 · see citing works
Physiological, Pathophysiological and Therapeutic Roles of Heparin and Heparan Sulfate
Xie, J., Murugesan, S., & Linhardt, R. J. (2008) · Elsevier eBooks · doi:10.1016/b978-0-08-054816-6.00010-0 · Cited by 4 · see citing works
Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
Wang, C., Yin, L., Fu, P., Lu, G., Zhai, X., & Yang, C. (2023) · Open Medicine · doi:10.1515/med-2023-0767 · Cited by 4 · see citing works
Apolipoprotein E Recognizes Alzheimer's Disease Associated 3‐O Sulfation of Heparan Sulfate
Mah, D., Zhu, Y., Su, G., Zhao, J., Canning, A., Gibson, J. M., Song, X., Stancanelli, E., Xu, Y., Zhang, F., et al. (2023) · Angewandte Chemie · doi:10.1002/ange.202212636 · Cited by 3 · see citing works
[A short discharge letter with a copy to the patient--satisfactory for patients and practitioners].
Nielsen, F. T., Rosholm, J.-U., Søndergaard, J., Gohr, T., & Tougaard, L. (1994) · PubMed · Cited by 3 · see citing works
Goldkamp, A. K., Kaplan, B. S., Menghwar, H., Kanipe, C. R., Boggiatto, P. M., Crawford, L. S., Olsen, S. C., Briggs, R. E., Tatum, F. M., Dassanayake, R. P., et al. (2025) · Frontiers in Veterinary Science · doi:10.3389/fvets.2025.1667623 · Cited by 2 · see citing works
Lombard, E., Marin, V., Domingo, N., Grès, S., Lorec, A., Saunier, V., Arlotto, E., Portugal, H., Lairon, D., Farnarier, C., et al. (2005) · Pathobiology · doi:10.1159/000086791 · Cited by 2 · see citing works
Jeevanandam, J., & Saraswathi, N. T. (2025) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2025.2584338 · Cited by 1 · see citing works
Nawabi, A. Q., Yang, M., Cai, X., Gou, W., Hou, J., Nizami, V., & Dai, Q. (2019) · World Journal of Cardiovascular Diseases · doi:10.4236/wjcd.2019.911074 · Cited by 1 · see citing works
Heparan Sulfate in the Amyloidosis and Inflammation of Alzheimer’s Disease
O′Callaghan, P. W. (2011) · KTH Publication Database DiVA (KTH Royal Institute of Technology) · Cited by 1 · see citing works
Alzheimer’s Disease Therapeutics Targeting Apolipoprotein E
Liao, F., & Holtzman, D. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00010-1
Hanbouch, L. (2017) · theses.fr (ABES) · doi:10.70675/c4d2c894zf69dz4ae4z9ab1zf4135d0efa12
Namba, N., Ariyoshi, S., Shimba, A., Shiroshita, H., Ohgita, T., & Saito, H. (2026) · ACS Omega · doi:10.1021/acsomega.6c09295
Self-citationThe Functional and Structural Analysis of a Mimetic Peptide of Human Hepatic Lipase
Coady, B. M., Courage, E. R., Fitzpatrick, M. N., Hickey, K. E., Booth, V. K., & Brown, R. (2015) · The FASEB Journal · doi:10.1096/fasebj.29.1_supplement.890.16
- Authors
- Saito, H., Dhanasekaran, P., Nguyen, D., Baldwin, F., Weisgraber, K. H., Wehrli, S., Phillips, M. C., & Lund-Katz, S.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University of California, San Francisco (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-04
- Volume
- 278
- Issue
- 17
- Pages
- 14782-14787
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2008655430
- Cited by
- 90
- References
- 53
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 6 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 1
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-41633, P01HL041633, R01HL056083, HL-56083)
- 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, heparin binding, heparan sulfate proteoglycans, electrostatic potential, N-terminal domain, C-terminal domain, biglycan, APOE3, point mutations
- MeSH terms
- Apolipoproteins E, Binding Sites, Heparin, Humans, Lipids, Mutation, Phosphatidylcholines, Protein Binding, Protein Structure, Tertiary, Nuclear Magnetic Resonance, Biomolecular, Amino Acids, Basic
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