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• W2006599070 abstract "Apolipoprotein (apo) E has roles beyond lipoprotein metabolism. The detrimental effects of apoE4 in cardiovascular, neurological, and infectious diseases correlate with its structural features (e.g., domain interaction) that distinguish it from apoE3 and apoE2. Structure/function studies revealed that apoE2 is severely defective in LDL receptor binding because of a structural difference that alters the receptor binding region and helped unravel the mechanism of type III hyperlipoproteinemia. ApoE4 is the major genetic risk factor for Alzheimer's disease and sets the stage for neuropathological disorders precipitated by genetic, metabolic, and environmental stressors. ApoE also influences susceptibility to parasitic, bacterial, and viral infections. In HIV-positive patients, apoE4 homozygosity hastens progression to AIDS and death and increases susceptibility to opportunistic infections. The next phase in our understanding of apoE will be characterized by clinical intervention to prevent or reverse the detrimental effects of apoE4 by modulating its structure or blocking the pathological processes it mediates. Apolipoprotein (apo) E has roles beyond lipoprotein metabolism. The detrimental effects of apoE4 in cardiovascular, neurological, and infectious diseases correlate with its structural features (e.g., domain interaction) that distinguish it from apoE3 and apoE2. Structure/function studies revealed that apoE2 is severely defective in LDL receptor binding because of a structural difference that alters the receptor binding region and helped unravel the mechanism of type III hyperlipoproteinemia. ApoE4 is the major genetic risk factor for Alzheimer's disease and sets the stage for neuropathological disorders precipitated by genetic, metabolic, and environmental stressors. ApoE also influences susceptibility to parasitic, bacterial, and viral infections. In HIV-positive patients, apoE4 homozygosity hastens progression to AIDS and death and increases susceptibility to opportunistic infections. The next phase in our understanding of apoE will be characterized by clinical intervention to prevent or reverse the detrimental effects of apoE4 by modulating its structure or blocking the pathological processes it mediates. Structural differences in apolipoprotein (apo) E isoforms impact cardiovascular, neurological, and infectious diseases (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 4Mahley R.W. Weisgraber K.H. Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2006; 103: 5644-5651Crossref PubMed Scopus (745) Google Scholar). Discovered in the 1970s, this 34-kDa, 299-amino-acid protein was identified in triglyceride-rich lipoproteins and induced by cholesterol feeding in animal models and humans (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 5Shore V.G. Shore B. Heterogeneity of human plasma very low density lipoproteins. Separation of species differing in protein components.Biochemistry. 1973; 12: 502-507Crossref PubMed Scopus (235) Google Scholar, 6Mahley R.W. Development of accelerated atherosclerosis. Concepts derived from cell biology and animal model studies.Arch. Pathol. Lab. Med. 1983; 107: 393-399PubMed Google Scholar). The three common isoforms (apoE2, apoE3, and apoE4) are encoded by a gene on chromosome 19. The three alleles differ in their frequencies: ε4 (15–20%), ε3 (65–70%), and ε2 (5–10%) and give rise to three homozygous and three heterozygous phenotypes. The nomenclature arose by consensus among key investigators (7Zannis V.I. Breslow J.L. Utermann G. Mahley R.W. Weisgraber K.H. Havel R.J. Goldstein J.L. Brown M.S. Schonfeld G. Hazzard W.R. al et Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes.J. Lipid Res. 1982; 23: 911-914Abstract Full Text PDF PubMed Google Scholar). Utermann, Hees, and Steinmetz (8Utermann G. Hees M. Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man.Nature. 1977; 269: 604-607Crossref PubMed Scopus (527) Google Scholar) recognized differences in the apoE isoform patterns that distinguished normolipidemic subjects from patients with the genetic lipid disorder type III hyperlipoproteinemia (HLP) (dysbetalipoproteinemia). Studies by Zannis, Breslow, Havel, and others (9Zannis V.I. Just P.W. Breslow J.L. Human apolipoprotein E isoprotein subclasses are genetically determined.Am. J. Hum. Genet. 1981; 33: 11-24PubMed Google Scholar, 10Havel R.J. Kane J.P. Primary dysbetalipoproteinemia: predominance of a specific apoprotein species in triglyceride-rich lipoproteins.Proc. Natl. Acad. Sci. USA. 1973; 70: 2015-2019Crossref PubMed Scopus (150) Google Scholar) helped unravel the isoform pattern. Ultimately, apoE2 was associated with type III HLP. Gladstone investigators elucidated the structural basis for the polymorphism of apoE and showed that apoE isoforms differ at two sites: apoE3 has Cys-112 and Arg-158, whereas apoE4 has arginines at both sites, and apoE2 has cysteines (11Weisgraber K.H. Rall Jr., S.C. Mahley R.W. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms.J. Biol. Chem. 1981; 256: 9077-9083Abstract Full Text PDF PubMed Google Scholar, 12Rall S.C., Jr. Weisgraber K.H. Mahley R.W. Human apolipoprotein E. The complete amino acid sequence.J. Biol. Chem. 1982; 257: 4171-4178Abstract Full Text PDF PubMed Google Scholar). They also determined the structure of apoE mRNA and the 3.6-kb gene encoding apoE and elucidated the regulatory elements that control its expression (13Taylor J.M. Simonet W.S. Lauer S.J. Zhu G. Walker D. Regulation and expression of the human apolipoprotein E gene in transgenic mice.Curr. Opin. Lipidol. 1993; 4: 84-89Crossref Scopus (11) Google Scholar, 14Grehan S. Tse E. Taylor J.M. Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain.J. Neurosci. 2001; 21: 812-822Crossref PubMed Google Scholar, 15Allan C.M. Taylor S. Taylor J.M. Two hepatic enhancers, HCR.1 and HCR.2, coordinate the liver expression of the entire human apolipoprotein E/C-I/C-IV/C-II gene cluster.J. Biol. Chem. 1997; 272: 29113-29119Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Plasma apoE (∼40–70 μg/ml) arises primarily from hepatic synthesis (>75%). The second most common site of synthesis is the brain (16Elshourbagy N.A. Liao W.S. Mahley R.W. Taylor J.M. Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets.Proc. Natl. Acad. Sci. USA. 1985; 82: 203-207Crossref PubMed Scopus (395) Google Scholar). Although astrocytes produce a large proportion of cerebrospinal fluid apoE (∼3–5 μg/ml), neurons synthesize apoE when stressed (17Xu Q. Bernardo A. Walker D. Kanegawa T. Mahley R.W. Huang Y. Profile and regulation of apolipoprotein E (apoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the apoE locus.J. Neurosci. 2006; 26: 4985-4994Crossref PubMed Scopus (332) Google Scholar). Macrophages and other cell types also synthesize apoE (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 16Elshourbagy N.A. Liao W.S. Mahley R.W. Taylor J.M. Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets.Proc. Natl. Acad. Sci. USA. 1985; 82: 203-207Crossref PubMed Scopus (395) Google Scholar). Initially, apoE was shown to be involved in lipid transport and cardiovascular disease (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar). It is the critical ligand in the plasma clearance of triglyceride- and cholesterol-rich lipoproteins (chylomicron remnants, VLDL, intermediate density lipoproteins, and a subclass of HDL). After Goldstein and Brown (18Goldstein J.L. Brown M.S. The LDL pathway in human fibroblasts: a receptor-mediated mechanism for the regulation of cholesterol metabolism.Curr. Top. Cell. Regul. 1976; 11: 147-181Crossref PubMed Scopus (121) Google Scholar) identified the LDL receptor, Gladstone investigators showed that apoE is the major ligand (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 19Innerarity T.L. Mahley R.W. Enhanced binding by cultured human fibroblasts of apo-E-containing lipoproteins as compared with low density lipoproteins.Biochemistry. 1978; 17: 1440-1447Crossref PubMed Scopus (250) Google Scholar, 20Innerarity T.L. Pitas R.E. Mahley R.W. Binding of arginine-rich (E) apoprotein after recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts.J. Biol. Chem. 1979; 254: 4186-4190Abstract Full Text PDF PubMed Google Scholar). It is also the ligand for other members of the LDL receptor family, including the LDL-receptor-related protein, which contributes to remnant lipoprotein clearance. ApoE binds to heparan sulfate proteoglycans (HSPG), which also clear apoE-containing remnant lipoproteins (3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 21Mahley R.W. Huang Y. Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing.J. Clin. Invest. 2007; 117: 94-98Crossref PubMed Scopus (123) Google Scholar). Studies of type III HLP were pivotal in elucidating the roles of apoE in remnant lipoprotein metabolism and atherosclerosis (3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 22Mahley R.W. Huang Y. Rall Jr., S.C. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes.J. Lipid Res. 1999; 40: 1933-1949Abstract Full Text Full Text PDF PubMed Google Scholar). ApoE also has a key role in neurobiology and Alzheimer’s disease (AD) (4Mahley R.W. Weisgraber K.H. Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2006; 103: 5644-5651Crossref PubMed Scopus (745) Google Scholar). It is critical for lipid transport in the brain and contributes to neuronal maintenance and repair. ApoE4 is the major genetic risk factor for AD, and 60–80% of AD patients have at least one apoE4 allele. ApoE also modulates susceptibility to infectious disease and possibly immunoregulation (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar). ApoE4 enhances the infectivity of HIV in vitro and hastens progression to AIDS and death in HIV-positive subjects (23Burt T.D. Agan B.K. Marconi V.C. He W. Kulkarni H. Mold J.E. Cavrois M. Huang Y. Mahley R.W. Dolan M.J. al et Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE ε4/ε4 genotype accelerates HIV disease progression.Proc. Natl. Acad. Sci. USA. 2008; 105: 8718-8723Crossref PubMed Scopus (161) Google Scholar). Structural analyses provided insight into the mechanisms of apoE’s involvement in cardiovascular, neurological, and infectious diseases (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 4Mahley R.W. Weisgraber K.H. Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2006; 103: 5644-5651Crossref PubMed Scopus (745) Google Scholar). ApoE has two structural domains separated by a hinge region (Fig. 1A). The N-terminal domain (amino acids 1–191) contains the receptor binding region (amino acids 134–150 and Arg-172) (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 24Morrow J.A. Arnold K.S. Dong J. Balestra M.E. Innerarity T.L. Weisgraber K.H. Effect of arginine 172 on the binding of apolipoprotein E to the low density lipoprotein receptor.J. Biol. Chem. 2000; 275: 2576-2580Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) and forms a four-helix antiparallel bundle (3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 25Wilson C. Wardell M.R. Weisgraber K.H. Mahley R.W. Agard D.A. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E.Science. 1991; 252: 1817-1822Crossref PubMed Scopus (601) Google Scholar). The C-terminal domain (amino acids ∼225–299) contains the major lipid binding region (amino acids ∼244–272) (2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar). The amino acid differences among the isoforms profoundly affect their structures and roles in disease. ApoE2 and apoE4 increase the number of atherogenic lipoproteins and accelerate atherogenesis (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 6Mahley R.W. Development of accelerated atherosclerosis. Concepts derived from cell biology and animal model studies.Arch. Pathol. Lab. Med. 1983; 107: 393-399PubMed Google Scholar). Understanding structural differences in apoE isoforms helped establish the molecular mechanism responsible for the associated pathology. First, the altered structure and impaired function of the receptor binding region of apoE2 increase triglyceride and cholesterol levels caused by delayed clearance of hepatic and intestinal remnant lipoproteins (β-VLDL), resulting in type III HLP (3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 22Mahley R.W. Huang Y. Rall Jr., S.C. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes.J. Lipid Res. 1999; 40: 1933-1949Abstract Full Text Full Text PDF PubMed Google Scholar). Cys-158 in apoE2 affects the receptor binding region by altering salt bridges and lowering the positive potential (25Wilson C. Wardell M.R. Weisgraber K.H. Mahley R.W. Agard D.A. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E.Science. 1991; 252: 1817-1822Crossref PubMed Scopus (601) Google Scholar). Second, the increase in plasma cholesterol, LDL, and apoB associated with apoE4 appears to reflect the influence of Arg-112 (1Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3395) Google Scholar, 2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar). Arg-112 alters the lipid binding region of apoE4 and changes the lipid binding preference from small phospholipid-rich HDL (apoE2 and apoE3) to large triglyceride-rich VLDL (apoE4). This difference is due to apoE4 domain interaction, in which the N- and C-terminal domains interact, resulting in a more compact structure. The receptor and proteoglycan binding regions were identified through structural studies of apoE2 and its role in type III HLP (3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 22Mahley R.W. Huang Y. Rall Jr., S.C. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes.J. Lipid Res. 1999; 40: 1933-1949Abstract Full Text Full Text PDF PubMed Google Scholar). Before the structure was delineated, arginine and lysine basic residues were shown to be critical for binding to the LDL receptor (26Mahley R.W. Innerarity T.L. Pitas R.E. Weisgraber K.H. Brown J.H. Gross E. Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B apoproteins.J. Biol. Chem. 1977; 252: 7279-7287Abstract Full Text PDF PubMed Google Scholar, 27Weisgraber K.H. Innerarity T.L. Mahley R.W. Role of the lysine residues of plasma lipoproteins in high affinity binding to cell surface receptors on human fibroblasts.J. Biol. Chem. 1978; 253: 9053-9062Abstract Full Text PDF PubMed Google Scholar). In addition, binding to phospholipids was required for high-affinity binding activity (20Innerarity T.L. Pitas R.E. Mahley R.W. Binding of arginine-rich (E) apoprotein after recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts.J. Biol. Chem. 1979; 254: 4186-4190Abstract Full Text PDF PubMed Google Scholar). Mutagenesis studies identified the critical basic residues within the 134–150 region of apoE as well as Arg-172 (24Morrow J.A. Arnold K.S. Dong J. Balestra M.E. Innerarity T.L. Weisgraber K.H. Effect of arginine 172 on the binding of apolipoprotein E to the low density lipoprotein receptor.J. Biol. Chem. 2000; 275: 2576-2580Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 28Lalazar A. Weisgraber K.H. Rall Jr., S.C. Giladi H. Innerarity T.L. Levanon A.Z. Boyles J.K. Amit B. Gorecki M. Mahley R.W. al et Site-specific mutagenesis of human apolipoprotein E. Receptor binding activity of variants with single amino acid substitutions.J. Biol. Chem. 1988; 263: 3542-3545Abstract Full Text PDF PubMed Google Scholar). Modeling of apoE into the molecular envelope of apoE bound to phospholipid revealed why lipid binding is required for high-affinity binding to LDL receptors (29Peters-Libeu C.A. Newhouse Y. Hatters D.M. Weisgraber K.H. Model of biologically active apolipoprotein E bound to dipalmitoylphosphatidylcholine.J. Biol. Chem. 2006; 281: 1073-1079Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). To fit the molecular envelope, apoE folded into a helical horseshoe, bringing the critical residues for binding, amino acids 134–150 and Arg-172, into close proximity (Fig. 1B). ApoE2, which is severely defective in LDL receptor binding activity (<2% LDL receptor binding activity compared with apoE3), differs structurally from apoE3 and apoE4, which bind avidly to LDL receptors. In apoE3, the 134–150 region is largely solvent exposed and forms a 20å field of positive potential, likely available for receptor binding. In apoE2, the presence of Cys-158 rather than arginine alters the conformation and size of the positive potential (3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar, 25Wilson C. Wardell M.R. Weisgraber K.H. Mahley R.W. Agard D.A. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E.Science. 1991; 252: 1817-1822Crossref PubMed Scopus (601) Google Scholar). Residue 158 lies outside the 134–150 region, so how does it influence binding activity? In apoE3, Arg-158 forms a salt bridge with Asp-154. However, in apoE2, Cys-158 disrupts the salt bridge, causing Asp-154 to interact with Arg-150 (30Dong L-M. Parkin S. Trakhanov S.D. Rupp B. Simmons T. Arnold K.S. Newhouse Y.M. Innerarity T.L. Weisgraber K.H. Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia.Nat. Struct. Biol. 1996; 3: 718-722Crossref PubMed Scopus (111) Google Scholar) (Fig. 2A). This alters the size of the positively charged domain and disrupts LDL receptor binding. Nevertheless, apoE2 can still mediate lipoprotein clearance through binding HSPG (21Mahley R.W. Huang Y. Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing.J. Clin. Invest. 2007; 117: 94-98Crossref PubMed Scopus (123) Google Scholar). Although apoE2 homozygosity is essential for type III HLP, the disorder is precipitated by genetic or environmental factors that result in saturated or impaired normal clearance pathways. These factors include estrogen deficiency, which can impair lipolytic processing; hypothyroidism, associated with decreased expression of LDL receptors; and obesity and diabetes, characterized by increased lipoprotein production. Transgenic mouse models expressing apoE2 provided proof of concept for how second “hits” induce type III HLP and how the hyperlipidemia is influenced by overproduction of apoB-containing lipoproteins and decreased numbers of LDL receptors (31Huang Y. Rall Jr., S.C. Mahley R.W. Genetic factors precipitating type III hyperlipoproteinemia in hypolipidemic transgenic mice expressing human apolipoprotein E2.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2817-2824Crossref PubMed Scopus (28) Google Scholar). In summary, understanding the structural differences among apoE2, apoE3, and apoE4 helped to unravel the complexity of type III HLP and, at the same time, defined the receptor binding region and lipoprotein clearance pathways. The C-terminal domain of apoE (amino acids 225–299) is predicted to form amphipathic α-helices (2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar). These helices are responsible for lipid binding in different apolipoproteins, and amino acids 244–272 constitute the lipid binding region of apoE (2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar, 3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar). ApoE3 and apoE2 preferentially bind to small, phospholipid-rich HDL, whereas apoE4 binds to large, triglyceride-rich VLDL. The difference is determined by how the N- and C-terminal domains interact (32Dong L-M. Weisgraber K.H. Human apolipoprotein E4 domain interaction. Arginine 61 and glutamic acid 255 interact to direct the preference for very low density lipoproteins.J. Biol. Chem. 1996; 271: 19053-19057Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar). X-ray crystallographic analyses of apoE3 and apoE4 revealed differences in side chain orientation and rearrangements of salt bridges. In apoE4, Arg-112 forms a salt bridge with Glu-109 and causes the Arg-61 side chain to extend away from the four-helix bundle. In apoE3, this side chain is buried (25Wilson C. Wardell M.R. Weisgraber K.H. Mahley R.W. Agard D.A. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E.Science. 1991; 252: 1817-1822Crossref PubMed Scopus (601) Google Scholar) (Fig. 2B). The orientation of Arg-61 in apoE4 promotes domain interaction by interacting with Glu-255 within the lipid binding region, causing apoE4 to have a more compact conformation than apoE3 (Fig. 1A) (32Dong L-M. Weisgraber K.H. Human apolipoprotein E4 domain interaction. Arginine 61 and glutamic acid 255 interact to direct the preference for very low density lipoproteins.J. Biol. Chem. 1996; 271: 19053-19057Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 33Dong L-M. Wilson C. Wardell M.R. Simmons T. Mahley R.W. Weisgraber K.H. Agard D.A. Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms.J. Biol. Chem. 1994; 269: 22358-22365Abstract Full Text PDF PubMed Google Scholar). Domain interaction is an important structural property of apoE4 (34Xu Q. Brecht W.J. Weisgraber K.H. Mahley R.W. Huang Y. Apolipoprotein E4 domain interaction occurs in living neuronal cells as determined by fluorescence resonance energy transfer.J. Biol. Chem. 2004; 279: 25511-25516Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 35Hatters D.M. Budamagunta M.S. Voss J.C. Weisgraber K.H. Modulation of apolipoprotein E structure by domain interaction. Differences in lipid-bound and lipid-free forms.J. Biol. Chem. 2005; 280: 34288-34295Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar) that may be responsible for several of its pathogenic effects. ApoE3 and apoE2 are less likely to demonstrate domain interaction. Mutation of Arg-61 to threonine, or Glu-255 to alanine, abolishes domain interaction, causing the mutated apoE4 to function similarly to apoE3 (36Ye S. Huang Y. Dong K.Mu¨llendorff, L. Giedt G. Meng E.C. Cohen F.E. Kuntz I.D. Weisgraber K.H. Mahley R.W. Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target.Proc. Natl. Acad. Sci. USA. 2005; 102: 18700-18705Crossref PubMed Scopus (223) Google Scholar). Domain interaction appears to alter the lipid binding region and, thus, lipoprotein preference. ApoE4 with Thr-61 corrects not only lipid binding preference but also several of the detrimental effects of apoE4 in neurobiology (4Mahley R.W. Weisgraber K.H. Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2006; 103: 5644-5651Crossref PubMed Scopus (745) Google Scholar). In most animals, including great apes, apoE has Arg-112 (like human apoE4) but has threonine at a site equivalent to Arg-61 in human apoE (2Weisgraber K.H. Apolipoprotein E: structure–function relationships.Adv. Protein Chem. 1994; 45: 249-302Crossref PubMed Google Scholar). Lacking domain interaction, it behaves like apoE3. Gene targeting to replace Thr-61 with arginine in mouse Apoe (37Raffai¨ R.L. Dong L-M. Farese Jr., R.V. Weisgraber K.H. Introduction of human apolipoprotein E4 “domain interaction” into mouse apolipoprotein E.Proc. Natl. Acad. Sci. USA. 2001; 98: 11587-11591Crossref PubMed Scopus (152) Google Scholar) produced a model of domain interaction (Arg-61 apoE mouse) that does not display other apoE4 structural properties. It established that domain interaction was responsible for the preference of apoE4 for VLDL. ApoE4 increases plasma LDL levels and risk for atherosclerosis and is overrepresented in hyperlipidemic and cardiovascular disease patients (3Mahley R.W. Rall Jr., S.C. Apolipoprotein E: far more than a lipid transport protein.Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1344) Google Scholar). Because apoE4 binds preferentially to VLDL and remnants, it may accelerate their clearance, leading to downregulation of LDL receptors and" @default.
• W2006599070 created "2016-06-24" @default.
• W2006599070 creator A5024330806 @default.
• W2006599070 creator A5033190041 @default.
• W2006599070 creator A5036108557 @default.
• W2006599070 date "2009-04-01" @default.
• W2006599070 modified "2023-10-17" @default.
• W2006599070 title "Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS" @default.
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• W2006599070 doi "https://doi.org/10.1194/jlr.r800069-jlr200" @default.
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