| Structural highlights
Disease
[APOE_HUMAN] Defects in APOE are a cause of hyperlipoproteinemia type 3 (HLPP3) [MIM:107741]; also known as familial dysbetalipoproteinemia. Individuals with HLPP3 are clinically characterized by xanthomas, yellowish lipid deposits in the palmar crease, or less specific on tendons and on elbows. The disorder rarely manifests before the third decade in men. In women, it is usually expressed only after the menopause. The vast majority of the patients are homozygous for APOE*2 alleles. More severe cases of HLPP3 have also been observed in individuals heterozygous for rare APOE variants. The influence of APOE on lipid levels is often suggested to have major implications for the risk of coronary artery disease (CAD). Individuals carrying the common APOE*4 variant are at higher risk of CAD.[1] [2] [3] [4] [5] Genetic variations in APOE are associated with Alzheimer disease type 2 (AD2) [MIM:104310]. It is a late-onset neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. Note=The APOE*4 allele is genetically associated with the common late onset familial and sporadic forms of Alzheimer disease. Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE*4 alleles in 42 families with late onset AD. Thus APOE*4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE*4 was virtually sufficient to cause AD by age 80. The mechanism by which APOE*4 participates in pathogenesis is not known.[6] Defects in APOE are a cause of sea-blue histiocyte disease (SBHD) [MIM:269600]; also known as sea-blue histiocytosis. This disorder is characterized by splenomegaly, mild thrombocytopenia and, in the bone marrow, numerous histiocytes containing cytoplasmic granules which stain bright blue with the usual hematologic stains. The syndrome is the consequence of an inherited metabolic defect analogous to Gaucher disease and other sphingolipidoses.[7] [8] [9] Defects in APOE are a cause of lipoprotein glomerulopathy (LPG) [MIM:611771]. LPG is an uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries. It mainly affects people of Japanese and Chinese origin. The disorder has rarely been described in Caucasians.[10] [11] [12] [13] Defects in APOE are a cause of familial hypercholesterolemia (FH) [MIM:143890]. FH is a condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.[14] [15]
Function
[APOE_HUMAN] Mediates the binding, internalization, and catabolism of lipoprotein particles. It can serve as a ligand for the LDL (apo B/E) receptor and for the specific apo-E receptor (chylomicron remnant) of hepatic tissues.
Publication Abstract from PubMed
Structures of apoE(263-286) and apoE(267-289) have been determined in aqueous solution containing 90-fold molar excess of perdeuterated sodium dodecyl sulfate by CD and 1H NMR. Conformations were calculated by distance geometry based on 370 and 276 NOE distance restraints, respectively. RMSD for superimposing the region 265-284 from an ensemble of 41 structures for apoE(263-286) is 0.64 +/- 0.17 A for backbone atoms (N, C alpha, C = O) and 1.51 +/- 0.13 A for all atoms. The backbone RMSD for an ensemble of 37 structures for apoE(267-289) is 0.74 +/- 0.21 A for the region 268-275 and 0.34 +/- 0.10 A for the region 276-286. A two-domain structure was found for apoE(267-289) with the C-terminal half adopting a very well defined helix and the N-terminal segment 268-275 a less well defined helix, suggesting that the N-terminus may weakly bind to SDS. For apoE(263-286), an amphipathic helix-bend-helix structural motif was found with all hydrophobic side chains on the concave face. The existence of a bend around residues Q273 to G278 is consistent with their temperature coefficients of amide protons as well as secondary shifts of alpha-protons. Comparison of the structures of the two peptides revealed that the enhanced binding of apoE(263-286) to lipid could be attributed to the formation of a hydrophobic cluster consisting of residues W264, F265, L268, and V269. Aromatic side chains are proposed to be especially important in anchoring apolipoprotein fragments to micelles.
Conformations of human apolipoprotein E(263-286) and E(267-289) in aqueous solutions of sodium dodecyl sulfate by CD and 1H NMR.,Wang G, Pierens GK, Treleaven WD, Sparrow JT, Cushley RJ Biochemistry. 1996 Aug 13;35(32):10358-66. PMID:8756691[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PMID:8346443
- ↑ Wardell MR, Weisgraber KH, Havekes LM, Rall SC Jr. Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121-127. J Biol Chem. 1989 Dec 15;264(35):21205-10. PMID:2556398
- ↑ Lohse P, Mann WA, Stein EA, Brewer HB Jr. Apolipoprotein E-4Philadelphia (Glu13----Lys,Arg145----Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia. J Biol Chem. 1991 Jun 5;266(16):10479-84. PMID:1674745
- ↑ Richard P, Thomas G, de Zulueta MP, De Gennes JL, Thomas M, Cassaigne A, Bereziat G, Iron A. Common and rare genotypes of human apolipoprotein E determined by specific restriction profiles of polymerase chain reaction-amplified DNA. Clin Chem. 1994 Jan;40(1):24-9. PMID:8287539
- ↑ Solanas-Barca M, de Castro-Oros I, Mateo-Gallego R, Cofan M, Plana N, Puzo J, Burillo E, Martin-Fuentes P, Ros E, Masana L, Pocovi M, Civeira F, Cenarro A. Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia. Atherosclerosis. 2012 Jun;222(2):449-55. doi:, 10.1016/j.atherosclerosis.2012.03.011. Epub 2012 Mar 16. PMID:22481068 doi:10.1016/j.atherosclerosis.2012.03.011
- ↑ Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PMID:8346443
- ↑ Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PMID:8346443
- ↑ Nguyen TT, Kruckeberg KE, O'Brien JF, Ji ZS, Karnes PS, Crotty TB, Hay ID, Mahley RW, O'Brien T. Familial splenomegaly: macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (delta149 Leu)]. J Clin Endocrinol Metab. 2000 Nov;85(11):4354-8. PMID:11095479
- ↑ Faivre L, Saugier-Veber P, Pais de Barros JP, Verges B, Couret B, Lorcerie B, Thauvin C, Charbonnier F, Huet F, Gambert P, Frebourg T, Duvillard L. Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation. Eur J Hum Genet. 2005 Nov;13(11):1186-91. PMID:16094309 doi:5201480
- ↑ Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PMID:8346443
- ↑ Oikawa S, Matsunaga A, Saito T, Sato H, Seki T, Hoshi K, Hayasaka K, Kotake H, Midorikawa H, Sekikawa A, Hara S, Abe K, Toyota T, Jingami H, Nakamura H, Sasaki J. Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 1997 May;8(5):820-3. PMID:9176854
- ↑ Matsunaga A, Sasaki J, Komatsu T, Kanatsu K, Tsuji E, Moriyama K, Koga T, Arakawa K, Oikawa S, Saito T, Kita T, Doi T. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int. 1999 Aug;56(2):421-7. PMID:10432380 doi:kid572
- ↑ Rovin BH, Roncone D, McKinley A, Nadasdy T, Korbet SM, Schwartz MM. APOE Kyoto mutation in European Americans with lipoprotein glomerulopathy. N Engl J Med. 2007 Dec 13;357(24):2522-4. PMID:18077821 doi:10.1056/NEJMc072088
- ↑ Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PMID:8346443
- ↑ Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, Devillers M, Luc G, Lecerf JM, Tosolini L, Erlich D, Peloso GM, Stitziel N, Nitchke P, Jais JP, Abifadel M, Kathiresan S, Leren TP, Rabes JP, Boileau C, Varret M. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat. 2013 Jan;34(1):83-7. doi: 10.1002/humu.22215. Epub 2012 Oct 11. PMID:22949395 doi:10.1002/humu.22215
- ↑ Wang G, Pierens GK, Treleaven WD, Sparrow JT, Cushley RJ. Conformations of human apolipoprotein E(263-286) and E(267-289) in aqueous solutions of sodium dodecyl sulfate by CD and 1H NMR. Biochemistry. 1996 Aug 13;35(32):10358-66. PMID:8756691 doi:10.1021/bi960934t
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