ABCA1 p.Leu222Lys
| Predicted by SNAP2: | A: D (66%), C: D (63%), D: D (80%), E: D (80%), F: D (71%), G: D (80%), H: D (75%), I: D (63%), K: D (80%), M: N (53%), N: D (80%), P: D (91%), Q: D (75%), R: D (80%), S: D (71%), T: D (71%), V: N (66%), W: D (80%), Y: D (71%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D, |
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[hide] Probing the pathways of chylomicron and HDL metabo... Curr Opin Lipidol. 2004 Apr;15(2):151-66. Zannis VI, Chroni A, Kypreos KE, Kan HY, Cesar TB, Zanni EE, Kardassis D
Probing the pathways of chylomicron and HDL metabolism using adenovirus-mediated gene transfer.
Curr Opin Lipidol. 2004 Apr;15(2):151-66., [PMID:15017358]
Abstract [show]
PURPOSE OF THE REVIEW: This review clarifies the functions of key proteins of the chylomicron and the HDL pathways. RECENT FINDINGS: Adenovirus-mediated gene transfer of several apolipoprotein (apo)E forms in mice showed that the amino-terminal 1-185 domain of apoE can direct receptor-mediated lipoprotein clearance in vivo. Clearance is mediated mainly by the LDL receptor. The carboxyl-terminal 261-299 domain of apoE induces hypertriglyceridemia, because of increased VLDL secretion, diminished lipolysis and inefficient VLDL clearance. Truncated apoE forms, including apoE2-202, have a dominant effect in remnant clearance and may have future therapeutic applications for the correction of remnant removal disorders. Permanent expression of apoE and apoA-I following adenoviral gene transfer protected mice from atherosclerosis. Functional assays, protein cross-linking, and adenovirus-mediated gene transfer of apoA-I mutants in apoA-I deficient mice showed that residues 220-231, as well as the central helices of apoA-I, participate in ATP-binding cassette transporter A1-mediated lipid efflux and HDL biogenesis. Following apoA-I gene transfer, an amino-terminal deletion mutant formed spherical alpha-HDL, a double amino- and carboxyl-terminal deletion mutant formed discoidal HDL, and a carboxyl-terminal deletion mutant formed only pre-beta-HDL. The findings support a model of cholesterol efflux that requires direct physical interactions between apoA-I and ATP-binding cassette transporter A1, and can explain Tangier disease and other HDL deficiencies. SUMMARY: New insights are provided into the role of apoE in cholesterol and triglyceride homeostasis, and of apoA-I in the biogenesis of HDL. Clearance of the lipoprotein remnants and increase in HDL synthesis are obvious targets for therapeutic interventions.
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No. Sentence Comment
192 Mutations M3 (apoA-I[Leu211,214,218,219Val]) and M4 (apoA-I [Leu222Lys/Phe225,229Lys]), which inhibit the binding of apoA-I to HDL and the solubilization of multilamellar DMPC vesicles in vitro, are associated with low HDL and apoA-I levels in vivo.
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ABCA1 p.Leu222Lys 15017358:192:61
status: NEW[hide] The central helices of ApoA-I can promote ATP-bind... J Biol Chem. 2003 Feb 28;278(9):6719-30. Epub 2002 Dec 17. Chroni A, Liu T, Gorshkova I, Kan HY, Uehara Y, Von Eckardstein A, Zannis VI
The central helices of ApoA-I can promote ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux. Amino acid residues 220-231 of the wild-type ApoA-I are required for lipid efflux in vitro and high density lipoprotein formation in vivo.
J Biol Chem. 2003 Feb 28;278(9):6719-30. Epub 2002 Dec 17., [PMID:12488454]
Abstract [show]
We have mapped the domains of lipid-free apoA-I that promote cAMP-dependent and cAMP-independent cholesterol and phospholipid efflux. The cAMP-dependent lipid efflux in J774 mouse macrophages was decreased by approximately 80-92% by apoA-I[delta(185-243)], only by 15% by apoA-I[delta(1-41)] or apoA-I[delta(1-59)], and was restored to 75-80% of the wild-type apoA-I control value by double deletion mutants apoA-I[delta(1-41)delta(185-243)] and apoA-I[delta(1-59)delta(185-243)]. Similar results were obtained in HEK293 cells transfected with an ATP-binding cassette transporter A1 (ABCA1) expression plasmid. The double deletion mutant of apoA-I had reduced thermal and chemical stability compared with wild-type apoA-I. Sequential carboxyl-terminal deletions showed that cAMP-dependent cholesterol efflux was diminished in all the mutants tested, except the apoA-I[delta(232-243)] which had normal cholesterol efflux. In cAMP-untreated or in mock-transfected cells, cholesterol efflux was not affected by the amino-terminal deletions, but decreased by 30-40% and 50-65% by the carboxyl-terminal and double deletions, respectively. After adenovirus-mediated gene transfer in apoA-I-deficient mice, wild-type apoA-I and apoA-I[delta(1-41)] formed spherical high density lipoprotein (HDL) particles, whereas apoA-I[delta(1-41)delta(185-243)] formed discoidal HDL. The findings suggest that although the central helices of apoA-I alone can promote ABCA1-mediated lipid efflux, residues 220-231 are necessary to allow functional interactions between the full-length apoA-I and ABCA1 that are required for lipid efflux and HDL biogenesis.
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309 It has also been shown that substitution of the hydrophobic amino acids L222K, F225K, and F229K of apoA-I in this region diminishes the ability of apoA-I to associate with HDL and phospholipids in vitro (43).
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ABCA1 p.Leu222Lys 12488454:309:72
status: NEW306 It has also been shown that substitution of the hydrophobic amino acids L222K, F225K, and F229K of apoA-I in this region diminishes the ability of apoA-I to associate with HDL and phospholipids in vitro (43).
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ABCA1 p.Leu222Lys 12488454:306:72
status: NEW