| 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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: Apolipoprotein-E (apo-E), a 34kDa blood plasma protein, plays a key role in directing cholesterol transport via its interaction with the low density lipoprotein (LDL) receptor. The amino-terminal domain of apo-E forms an unusually elongated four-helix bundle arranged such that key basic residues involved in LDL receptor binding form a cluster at the end of one of the helices. A common apo-E variant, apo-E2, corresponding to the single-site substitution Arg158-->Cys, displays minimal LDL receptor binding and is associated with significant changes in plasma cholesterol levels and increased risk of coronary heart disease. Surprisingly, the site of mutation in this variant is physically well removed (> 12A) from the cluster of LDL receptor binding residues. RESULTS: We now report the refined crystal structure of the amino-terminal domain of apo-E2, at a nominal resolution of 3.0A. This structure reveals significant conformational changes relative to the wild-type protein that may account for reduced LDL receptor binding. Removal of the Arg158 side chain directly disrupts a pair of salt bridges, causing a compensatory reorganization of salt bridge partners that dramatically alters the charge surface presented by apo-E to its receptor. CONCLUSIONS: It is proposed that the observed reorganization of surface salt bridges is responsible for the decreased receptor binding by apo-E2. This reorganization, essentially functioning as a mutationally induced electrostatic switch to turn off receptor binding, represents a novel mechanism for the propagation of conformational changes over significant distances.
Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein.,Wilson C, Mau T, Weisgraber KH, Wardell MR, Mahley RW, Agard DA Structure. 1994 Aug 15;2(8):713-8. PMID:7994571[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
- ↑ Wilson C, Mau T, Weisgraber KH, Wardell MR, Mahley RW, Agard DA. Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein. Structure. 1994 Aug 15;2(8):713-8. PMID:7994571
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