Contributions of the Carboxyl-Terminal Helical Segment to the Self-Association and Lipoprotein Preferences of Human Apolipoprotein E3 and E4 Isoforms
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To understand the molecular basis for the different self-association and lipoprotein preferences of apolipoprotein (apo) E isoforms, we compared the effects of progressive truncation of the C-terminal domain in human apoE3 and apoE4 on their lipid-free structure and lipid binding properties. A VLDL/HDL distribution assay demonstrated that apoE3 binds much better than apoE4 to HDL 3, whereas both isoforms bind similarly to VLDL. Removal of the C-terminal helical regions spanning residues 273-299 weakened the ability of both isoforms to bind to lipoproteins; this led to the elimination of the isoform lipoprotein preference, indicating that the C-terminal helices mediate the lipoprotein selectivity of apoE3 and apoE4 isoforms. Gel filtration chromatography experiments demonstrated that the monomer-tetramer distribution is different for the two isoforms with apoE4 being more monomeric than apoE3 and that removal of the C-terminal helices favors the monomeric state in both isoforms. Consistent with this, fluorescence measurements of Trp-264 in single-Trp mutants revealed that the C-terminal domain in apoE4 is less organized and more exposed to the aqueous environment than in apoE3. In addition, the solubilization of dimyristoylphosphatidylcholine multilamellar vesicles is more rapid with apoE4 than with apoE3; removal of the C-terminal helices significantly affected solubilization rates with both isoforms. Taken together, these results indicate that the C-terminal domain is organized differently in apoE3 and apoE4 so that apoE4 self-associates less and binds less than apoE3 to HDL surfaces; these alterations may lead to the pathological sequelae for cardiovascular and neurodegenerative diseases.
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At a very low protein concentration (5 μg/ml), full-length apoE3 predominantly forms tetramer, more than half of apoE3 (1-272) forms tetramer, and apoE3 (1-260) exists completely as a monomer.
“Using gel filtration chromatography, we showed previously that, even at a very low protein concentration (5 μg/ml), full-length apoE3 predominantly forms tetramer and that more than half of apoE3 (1–272) forms tetramer whereas apoE3 (1–260) exists completely as a monomer (47).”
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 [47]
C-terminal helical residues 261-299 or 272-299 modulate the tetramerization of apoE in solution.
“Using C-terminally truncated mutants of apoE, we showed previously that the C-terminal helical residues, 261–299 or 272–299 modulate the tetramerization of apoE in solution (37, 47).”
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 [47]
ApoE self-associates through the C-terminal domain, and the C-terminal α-helical regions are responsible for the self-association.
“ApoE is known to self-associate through the C-terminal domain in solution and the C-terminal α-helical regions are responsible for the self-association (21, 45–47).”
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 [47]
It is unlikely that the higher binding ability of apoE4 to GAG is due to cooperative effects of the heparin binding sites.
“Since apoE4 has a lesser propensity to self-associate than apoE3 in solution (47) and the number of apoE molecules on DMPC discs is similar among apoE isoforms (52), it is unlikely that the higher ability of binding of apoE4 to GAG is due to the cooperative effects of the heparin binding sites.”
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 [47]
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Cites
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
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
Apolipoprotein E and Alzheimer disease.
Strittmatter, W. J., & Roses, A. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.11.4725 · Cited by 699 · 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
Mahley, 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
Apolipoprotein E-ε4 genotype predicts a poor outcome in survivors of traumatic brain injury
Friedman, G., Froom, P., Sazbon, L., Grinblatt, I., Shochina, M., Tsenter, J., Babaey, S., Yehuda, A. B., & Groswasser, Z. (1999) · Neurology · doi:10.1212/wnl.52.2.244 · Cited by 437 · 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
Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., Fish, J. D., Masliah, E., Hopkins, P. C., Scearce-Levie, K., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1434398100 · Cited by 342 · see citing works
Interaction of an apolipoprotein (apoLP-alanine) with phosphatidylcholine
Morrisett, J. D., David, J. S. K., Pownall, H. J., & Gotto, A. M. (1973) · Biochemistry · doi:10.1021/bi00731a008 · Cited by 331 · 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
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 · Cited by 320 · see citing works
Human Apolipoprotein E4 Domain Interaction
Dong, L.-M., & Weisgraber, K. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.32.19053 · Cited by 318 · see citing works
Morrow, J. A., Segall, M. L., Lund-Katz, S., Phillips, M. C., Knapp, M., Rupp, B., & Weisgraber, K. H. (2000) · Biochemistry · doi:10.1021/bi000099m · Cited by 315 · 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
Weisgraber, K. H. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42621-5 · Cited by 304 · see citing works
Human apolipoprotein E3 in aqueous solution. I. Evidence for two structural domains.
Wetterau, J. R., Aggerbeck, L. P., Rall, S. C., & Weisgraber, K. H. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68778-2 · Cited by 293 · see citing works
Domain Structure and Lipid Interaction in Human Apolipoproteins A-I and E, a General Model
Saito, H., Dhanasekaran, P., Nguyen, D., Holvoet, P., Lund‐Katz, S., & Phillips, M. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303365200 · Cited by 179 · see citing works
Self-citationWesterlund, J. A., & Weisgraber, K. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82318-3 · Cited by 164 · see citing works
Sparks, D. L., Lund‐Katz, S., & Phillips, M. C. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)35686-2 · Cited by 156 · see citing works
Self-citationMolecular basis of exchangeable apolipoprotein function
Narayanaswami, V., & Ryan, R. O. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(99)00176-6 · Cited by 152 · see citing works
Inter-molecular Coiled-coil Formation in Human Apolipoprotein E C-terminal Domain
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
Reactivity of Apolipoprotein E4 and Amyloid β Peptide
Ji, Z.-S., Müllendorff, K., Cheng, I. H., Miranda, R. D., Huang, Y., & Mahley, R. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m506646200 · Cited by 127 · see citing works
Liu, L., Bortnick, A. E., Nickel, M., Dhanasekaran, P., Subbaiah, P. V., Lund‐Katz, S., Rothblat, G. H., & Phillips, M. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308420200 · Cited by 121 · see citing works
Self-citationSelf-association of human apolipoprotein E3 and E4 in the presence and absence of phospholipid
Perugini, M. A., Schuck, P., & Howlett, G. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005565200 · Cited by 118 · see citing works
Behavior of human apolipoprotein E in aqueous solutions and at interfaces.
Yokoyama, S., Kawai, Y., Tajima, S., & Yamamoto, A. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36247-6 · 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-citationVedhachalam, C., Narayanaswami, V., Neto, N., Forte, T. M., Phillips, M. C., Lund‐Katz, S., & Bielicki, J. K. (2007) · Biochemistry · doi:10.1021/bi602407r · Cited by 106 · see citing works
Self-citationApolipoprotein E and Atherosclerosis
Davignon, J. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000154570.50696.2c · Cited by 100 · see citing works
Segall, M. L., Dhanasekaran, P., Baldwin, F., Anantharamaiah, G. M., Weisgraber, K. H., Phillips, M. C., & Lund‐Katz, S. (2002) · Journal of Lipid Research · doi:10.1194/jlr.m200157-jlr200 · Cited by 93 · 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-citationModulation of Apolipoprotein E Structure by Domain Interaction
Hatters, D. M., Budamagunta, M. S., Voss, J. C., & Weisgraber, K. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506044200 · Cited by 88 · see citing works
β‐Amyloid Peptide Interacts Specifically with the Carboxyl‐Terminal Domain of Human Apolipoprotein E
Pillot, T., Goethals, M., Najib, J., Labeur, C., Lins, L., Chambaz, J., Brasseur, R., Vandekerckhove, J. S., & Rosseneu, M. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0720230.x · Cited by 84 · see citing works
Mahley, R. W., & Huang, Y. (2006) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2006.00679.x · Cited by 82 · see citing works
Acharya, P., Segall, M. L., Zaiou, M., Morrow, J., Weisgraber, K. H., Phillips, M. C., Lund-Katz, S., & Snow, J. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(02)00263-9 · Cited by 82 · see citing works
Self-citationA Monomeric, Biologically Active, Full-Length Human Apolipoprotein E
Zhang, Y., Vasudevan, S., Sojitrawala, R., Zhao, W., Cui, C., Xu, C., Fan, D., Newhouse, Y., Balestra, R., Jerome, W. G., et al. (2007) · Biochemistry · doi:10.1021/bi700672v · Cited by 79 · see citing works
Apolipoprotein E and ALzheimer's Disease: The Tip of the Susceptibility Iceberg
Roses, A. D. (1998) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1998.tb10653.x · Cited by 78 · see citing works
Raffaı̈, R. L., & Weisgraber, K. H. (2003) · Journal of Lipid Research · doi:10.1194/jlr.r300007-jlr200 · Cited by 76 · see citing works
Saito, H., Minamida, T., Arimoto, I., Handa, T., & Miyajima, K. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.26.15515 · Cited by 57 · see citing works
Self-citationEffects 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
Li, X., Kypreos, K. E., Zanni, E. E., & Zannis, V. I. (2003) · Biochemistry · doi:10.1021/bi027093c · Cited by 49 · see citing works
Structural and functional variations in human apolipoprotein E3 and E4.
Chou, C.-Y., Jen, W.-P., Hsieh, Y.-H., Shiao, M.-S., & Chang, G.-G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511077200 · Cited by 46 · see citing works
Effect of Carboxyl-Terminal Truncation on Structure and Lipid Interaction of Human Apolipoprotein E4
Tanaka, M., Vedhachalam, C., Sakamoto, T., Dhanasekaran, P., Phillips, M. C., Lund-Katz, S., & Saito, H. (2006) · Biochemistry · doi:10.1021/bi060023b · Cited by 43 · see citing works
Self-citationA Monomeric Human Apolipoprotein E Carboxyl-Terminal Domain
Fan, D., Li, Q., Korando, L., Jerome, W. G., & Wang, J. (2004) · Biochemistry · doi:10.1021/bi035958w · Cited by 42 · 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-citationExamination of Lipid-bound Conformation of Apolipoprotein E4 by Pyrene Excimer Fluorescence
Drury, J., & Narayanaswami, V. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414019200 · Cited by 37 · 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
Use of fluorescence spectroscopy as thermodynamics tool
Eftink, M. R. (2000) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(00)23378-8 · Cited by 34 · see citing works
Phu, M.-J., Hawbecker, S. K., & Narayanaswami, V. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20503 · Cited by 21 · see citing works
Drosatos, K., Kypreos, K. E., & Zannis, V. I. (2007) · Biochemistry · doi:10.1021/bi700232g · Cited by 8 · see citing works
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Apolipoprotein E isoforms and lipoprotein metabolism
Phillips, M. C. (2014) · IUBMB Life · doi:10.1002/iub.1314 · Cited by 328 · see citing works
Self-citationApolipoprotein E and cholesterol in aging and disease in the brain
de Chaves, E. P., Narayanaswami, V., Christoffersen, C., & Nielsen, L. B. (2008) · Future Lipidology · doi:10.2217/17460875.3.5.505 · Cited by 164 · 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-citationArgyri, L., Dafnis, I., Theodossiou, T. A., Gantz, D., Stratikos, E., & Chroni, A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.538124 · Cited by 30 · see citing works
- Authors
- Sakamoto, T., Tanaka, M., Vedhachalam, C., Nickel, M., Nguyen, D., Dhanasekaran, P., Phillips, M. C., Lund-Katz, S., & Saito, H.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Department of Biophysical Chemistry, Kobe Pharmaceutical University, Kobe 658-8558, Japan, and Division of GI/Nutrition, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2008-01-18
- Volume
- 47
- Issue
- 9
- Pages
- 2968-2977
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC2692928
- OpenAlex
- W1986838916
- Cited by
- 54
- References
- 52
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 3
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL056083, HL-56083)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, APOE3, APOE ε4, self-association, lipoprotein binding, HDL cholesterol, VLDL, lipid binding, truncation mutants, cardiovascular disease, neurodegenerative diseases
- MeSH terms
- Chromatography, Gel, Circular Dichroism, Humans, Lipoproteins, Lipoproteins, HDL, Lipoproteins, VLDL, Protein Binding, Protein Conformation, Protein Denaturation, Protein Structure, Secondary, Protein Structure, Tertiary, Apolipoprotein E3, Apolipoprotein E4
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