ABCA1 p.Leu268Ala
| Predicted by SNAP2: | A: N (66%), C: N (61%), D: D (63%), E: N (57%), F: N (82%), G: D (53%), H: N (53%), I: N (82%), K: N (61%), M: N (78%), N: N (57%), P: D (63%), Q: N (66%), R: N (57%), S: N (66%), T: N (57%), V: N (82%), W: D (63%), Y: N (72%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Discrete roles of apoA-I and apoE in the biogenesi... Ann Med. 2008 Feb;40 Suppl 1:14-28. Zannis VI, Koukos G, Drosatos K, Vezeridis A, Zanni EE, Kypreos KE, Chroni A
Discrete roles of apoA-I and apoE in the biogenesis of HDL species: lessons learned from gene transfer studies in different mouse models.
Ann Med. 2008 Feb;40 Suppl 1:14-28., [PMID:18246469]
Abstract [show]
Using adenovirus-mediated gene transfer in apolipoprotein A-I (apoA-I)-deficient mice, we have established that apoA-I mutations inhibit discrete steps in a pathway that leads to the biogenesis and remodeling of high-density lipoprotein (HDL). To this point, five discrete categories of apoA-I mutants have been characterized that may affect the interactions of apoA-I with ATP-binding cassette superfamily A, member 1 (ABCA1) or lecithin:cholesterol acyl transferase (LCAT) or may influence the plasma phospholipid transfer protein activity or may cause various forms of dyslipidemia. Biogenesis of HDL is not a unique property of apoA-I. Using adenovirus-mediated gene transfer of apoE in apoA-I- or ABCA1-deficient mice, we have established that apolipoprotein E (apoE) also participates in a novel pathway of biogenesis of apoE-containing HDL particles. This process requires the functions of the ABCA1 lipid transporter and LCAT, and it is promoted by substitution of hydrophobic residues in the 261 to 269 region of apoE by Ala. The apoE-containing HDL particles formed in the circulation may have atheroprotective properties. ApoE-containing HDL may also have important biological functions in the brain that confer protection from Alzheimer's disease.
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No. Sentence Comment
149 A triple substitution (apoE4[Leu261Ala/Trp264Ala/Phe265Ala]) or five residue substitutions (apoE4[Leu261Ala/Trp264Ala/ Phe265Ala/Leu268Ala/Val269Ala]) did not induce hypertriglyceridemia and both were associated with greatly increased HDL cholesterol levels (Figure 8A III, B III and A IV, B IV, respectively) (19,20).
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ABCA1 p.Leu268Ala 18246469:149:129
status: NEW150 EM analysis of the HDL fractions showed that apoE4[Leu261Ala/Trp264Ala/Phe265Ala] and the apoE4[Leu261Ala/Trp264Ala/Phe265Ala/Leu268Ala/ Val269Ala] formed spherical HDL (Figure 8C III, IV), apoE4[Phe265Ala] formed discoidal HDL (Figure 8CI), and the apoE4[Leu261Ala/Trp264Ala] formed mostly spherical and few discoidal HDL particles (Figure 8C II) (20).
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ABCA1 p.Leu268Ala 18246469:150:126
status: NEW[hide] Pathway of biogenesis of apolipoprotein E-containi... Biochem J. 2007 Apr 15;403(2):359-67. Kypreos KE, Zannis VI
Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCAT.
Biochem J. 2007 Apr 15;403(2):359-67., [PMID:17206937]
Abstract [show]
We have investigated the ability of apoE (apolipoprotein E) to participate in the biogenesis of HDL (high-density lipoprotein) particles in vivo using adenovirus-mediated gene transfer in apoA-I-/- (apolipoprotein A-I) or ABCA1-/- (ATP-binding cassette A1) mice. Infection of apoA-I-/- mice with 2x10(9) pfu (plaque-forming units) of an apoE4-expressing adenovirus increased both HDL and the triacylglycerol-rich VLDL (very-low-density lipoprotein)/IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein) fraction and generated discoidal HDL particles. ABCA1-/- mice treated similarly failed to form HDL particles, suggesting that ABCA1 is essential for the generation of apoE-containing HDL. Combined infection of apoA-I-/- mice with a mixture of adenoviruses expressing both apoE4 (2x10(9) pfu) and human LCAT (lecithin:cholesterol acyltransferase) (5x10(8) pfu) cleared the triacylglycerol-rich lipoproteins, increased HDL and converted the discoidal HDL into spherical HDL. Similarly, co-infection of apoE-/- mice with apoE4 and human LCAT corrected the hypercholesterolaemia and generated spherical particles, suggesting that LCAT is essential for the maturation of apoE-containing HDL. Overall, the findings indicate that apoE has a dual functionality. In addition to its documented functions in the clearance of triacylglycerol-rich lipoproteins, it participates in the biogenesis of HDL-sized apoE-containing particles. HDL particles generated by this pathway may account at least for some of the atheroprotective functions of apoE.
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30 It is important to note that infection of apoA-I-/- mice with adenovirus expressing a recently described apoE4 (L261A/ W264A/F265A/L268A/V269A) mutant designated apoE4mut1 [17] did not induce dyslipidaemia and promoted the formation of spherical apoE-containing HDL particles, suggesting that this mutant has improved functions in lipoprotein clearance as well as in the biogenesis of apoE-containing HDL.
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ABCA1 p.Leu268Ala 17206937:30:131
status: NEW117 Substitution of alanine for hydrophobic residues in the region 261-269 enhances formation of spherical HDL and does not induce dyslipidaemia in apoA-I-/- mice In another set of experiments, apoA-I-/- mice were infected with 2 × 109 pfu of an adenovirus expressing the apoE4 mutant (L261A/W264A/F265A/L268A/V269A) mutant designated apoE4mut1 [17].
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ABCA1 p.Leu268Ala 17206937:117:305
status: NEW137 These experiments indicated that, under conditions of apoE overexpression, the endogenous Figure 4 Cholesterol FPLC profile, apoE distribution and electron microscopy analysis of HDL fraction of apoE-/- mice infected with recombinant adenoviruses expressing apoE4mut1 (A) FPLC profiles of total, free and esterified cholesterol of apoE-/- mice infected with 2 × 109 pfu of adenoviruses expressing apoE4mut1 (AdGFRP-E4[L261A,T264A,F265A, L268A,V269A]).
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ABCA1 p.Leu268Ala 17206937:137:445
status: NEW29 It is important to note that infection of apoA-I-/- mice with adenovirus expressing a recently described apoE4 (L261A/ W264A/F265A/L268A/V269A) mutant designated apoE4mut1 [17] did not induce dyslipidaemia and promoted the formation of spherical apoE-containing HDL particles, suggesting that this mutant has improved functions in lipoprotein clearance as well as in the biogenesis of apoE-containing HDL.
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ABCA1 p.Leu268Ala 17206937:29:131
status: NEW115 Substitution of alanine for hydrophobic residues in the region 261-269 enhances formation of spherical HDL and does not induce dyslipidaemia in apoA-I-/- mice In another set of experiments, apoA-I-/- mice were infected with 2 &#d7; 109 pfu of an adenovirus expressing the apoE4 mutant (L261A/W264A/F265A/L268A/V269A) mutant designated apoE4mut1 [17].
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ABCA1 p.Leu268Ala 17206937:115:304
status: NEW135 These experiments indicated that, under conditions of apoE overexpression, the endogenous Figure 4 Cholesterol FPLC profile, apoE distribution and electron microscopy analysis of HDL fraction of apoE-/- mice infected with recombinant adenoviruses expressing apoE4mut1 (A) FPLC profiles of total, free and esterified cholesterol of apoE-/- mice infected with 2 &#d7; 109 pfu of adenoviruses expressing apoE4mut1 (AdGFRP-E4[L261A,T264A,F265A, L268A,V269A]).
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ABCA1 p.Leu268Ala 17206937:135:444
status: NEW