ABCA1 p.Cys733Arg
| Predicted by SNAP2: | A: N (57%), D: D (91%), E: D (85%), F: D (91%), G: D (66%), H: D (80%), I: D (85%), K: D (91%), L: D (91%), M: D (85%), N: D (75%), P: D (91%), Q: D (85%), R: D (80%), S: N (66%), T: D (53%), V: D (85%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Apolipoprotein A-I-stimulated apolipoprotein E sec... J Biol Chem. 2004 Jun 18;279(25):25966-77. Epub 2004 Apr 1. Kockx M, Rye KA, Gaus K, Quinn CM, Wright J, Sloane T, Sviridov D, Fu Y, Sullivan D, Burnett JR, Rust S, Assmann G, Anantharamaiah GM, Palgunachari MN, Katz SL, Phillips MC, Dean RT, Jessup W, Kritharides L
Apolipoprotein A-I-stimulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux.
J Biol Chem. 2004 Jun 18;279(25):25966-77. Epub 2004 Apr 1., [PMID:15066991]
Abstract [show]
Apolipoprotein A-I (apoA-I)-mediated cholesterol efflux involves the binding of apoA-I to the plasma membrane via its C terminus and requires cellular ATP-binding cassette transporter (ABCA1) activity. ApoA-I also stimulates secretion of apolipoprotein E (apoE) from macrophage foam cells, although the mechanism of this process is not understood. In this study, we demonstrate that apoA-I stimulates secretion of apoE independently of both ABCA1-mediated cholesterol efflux and of lipid binding by its C terminus. Pulse-chase experiments using (35)S-labeled cellular apoE demonstrate that macrophage apoE exists in both relatively mobile (E(m)) and stable (E(s)) pools, that apoA-I diverts apoE from degradation to secretion, and that only a small proportion of apoA-I-mobilized apoE is derived from the cell surface. The structural requirements for induction of apoE secretion and cholesterol efflux are clearly dissociated, as C-terminal deletions in recombinant apoA-I reduce cholesterol efflux but increase apoE secretion, and deletion of central helices 5 and 6 decreases apoE secretion without perturbing cholesterol efflux. Moreover, a range of 11- and 22-mer alpha-helical peptides representing amphipathic alpha-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal alpha-helix (domains 220-241) stimulates cholesterol efflux. Other alpha-helix-containing apolipoproteins (apoA-II, apoA-IV, apoE2, apoE3, apoE4) also stimulate apoE secretion, implying a positive feedback autocrine loop for apoE secretion, although apoE4 is less effective. Finally, apoA-I stimulates apoE secretion normally from macrophages of two unrelated subjects with genetically confirmed Tangier Disease (mutations C733R and c.5220-5222delTCT; and mutations A1046D and c.4629-4630insA), despite severely inhibited cholesterol efflux. We conclude that apoA-I stimulates secretion of apoE independently of cholesterol efflux, and that this represents a novel, ABCA-1-independent, positive feedback pathway for stimulation of potentially anti-atherogenic apoE secretion by alpha-helix-containing molecules including apoA-I and apoE.
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No. Sentence Comment
7 Finally, apoA-I stimulates apoE secretion normally from macrophages of two unrelated subjects with genetically confirmed Tangier Disease (mutations C733R and c.5220-5222delTCT; and mutations A1046D and c.4629-4630insA), despite severely inhibited cholesterol efflux.
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ABCA1 p.Cys733Arg 15066991:7:148
status: NEW127 Two novel amino acid mutations within the ABCA1 gene were found: C733R in exon 16 (c.2197CϾT) and a deletion of three nucleotides in exon 38 (c.5220-5222delTCT) on different alleles as shown by segregation analysis (numbering follows recommendations of the international nomenclature working group).
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ABCA1 p.Cys733Arg 15066991:127:65
status: NEW310 The first subject with TD (TD1, see "Experimental Procedures"), was a compound heterozygote for the novel ABCA1 mutations C733R in exon 16 and a deletion of three nucleotides (c.5220-5222 delTCT) in exon 38 (TD1-HMDM).
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ABCA1 p.Cys733Arg 15066991:310:122
status: NEW348 Subject Mutation HDL-C Basal apoE secretion ApoA-I-specific cholesterol efflux ApoA-I-stimulated apoE secretion mg/dL g/mg cell protein g/mg cell protein Aa HC1 44.0b 2.2 Ϯ 0.49b 3.1 Ϯ 0.5b 6.3 Ϯ 0.9 TD1 C733R;C.5220-5222delTCT 3.1 0.5 Ϯ 0.21 0.5 Ϯ 0.5 5.6 Ϯ 1.2 Bc HC2 43.0d 1.1 Ϯ 1.6 2.2 Ϯ 0.4d 4.2 Ϯ 1.0 TD2d A1046D;4629insA 2.7 NDe 0.2 Ϯ 0.2 3.8 Ϯ 0.7 HZ2A 4629insA 25.8d ND 1.9 Ϯ 0.3d 2.6 Ϯ 0.6 HZ2B A1046D 38.6d 1.4 Ϯ 0.2 2.8 Ϯ 0.1d 4.5 Ϯ 0.9 a Part A: macrophages from newly characterized TD1 and unrelated control subject HC1 were compared for cholesterol efflux and apoE secretion in the presence and absence of 25 g/ml apoA-I. Cholesterol efflux and apoE secretion were determined at 8 h, and apoA-I-specific efflux derived by subtracting efflux to control medium (without A-I) from that to apoA-I. b Conditions are significantly different between HC1 and TD1, p Ͻ 0.01. c Part B: TD2 has previously been described (44).
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ABCA1 p.Cys733Arg 15066991:348:238
status: NEW128 Two novel amino acid mutations within the ABCA1 gene were found: C733R in exon 16 (c.2197Cb0e;T) and a deletion of three nucleotides in exon 38 (c.5220-5222delTCT) on different alleles as shown by segregation analysis (numbering follows recommendations of the international nomenclature working group).
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ABCA1 p.Cys733Arg 15066991:128:65
status: NEW309 The first subject with TD (TD1, see "Experimental Procedures"), was a compound heterozygote for the novel ABCA1 mutations C733R in exon 16 and a deletion of three nucleotides (c.5220-5222 delTCT) in exon 38 (TD1-HMDM).
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ABCA1 p.Cys733Arg 15066991:309:122
status: NEW346 Subject Mutation HDL-C Basal apoE secretion ApoA-I-specific cholesterol efflux ApoA-I-stimulated apoE secretion mg/dL òe;g/mg cell protein òe;g/mg cell protein Aa HC1 44.0b 2.2 afe; 0.49b 3.1 afe; 0.5b 6.3 afe; 0.9 TD1 C733R;C.5220-5222delTCT 3.1 0.5 afe; 0.21 0.5 afe; 0.5 5.6 afe; 1.2 Bc HC2 43.0d 1.1 afe; 1.6 2.2 afe; 0.4d 4.2 afe; 1.0 TD2d A1046D;4629insA 2.7 NDe 0.2 afe; 0.2 3.8 afe; 0.7 HZ2A 4629insA 25.8d ND 1.9 afe; 0.3d 2.6 afe; 0.6 HZ2B A1046D 38.6d 1.4 afe; 0.2 2.8 afe; 0.1d 4.5 afe; 0.9 a Part A: macrophages from newly characterized TD1 and unrelated control subject HC1 were compared for cholesterol efflux and apoE secretion in the presence and absence of 25 òe;g/ml apoA-I. Cholesterol efflux and apoE secretion were determined at 8 h, and apoA-I-specific efflux derived by subtracting efflux to control medium (without A-I) from that to apoA-I. b Conditions are significantly different between HC1 and TD1, p b0d; 0.01. c Part B: TD2 has previously been described (44).
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ABCA1 p.Cys733Arg 15066991:346:236
status: NEW