ABCA1 p.Ala1950Val
| Predicted by SNAP2: | C: N (53%), D: D (80%), E: D (85%), F: D (66%), G: D (63%), H: D (66%), I: D (71%), K: D (80%), L: D (75%), M: D (75%), N: D (71%), P: D (85%), Q: D (80%), R: D (85%), S: D (63%), T: D (71%), V: D (66%), W: D (80%), Y: D (75%), |
| Predicted by PROVEAN: | C: 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] ABCA1 mutants reveal an interdependency between li... J Lipid Res. 2009 Feb;50(2):285-92. Epub 2008 Sep 5. Vaughan AM, Tang C, Oram JF
ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation.
J Lipid Res. 2009 Feb;50(2):285-92. Epub 2008 Sep 5., [PMID:18776170]
Abstract [show]
ABCA1 exports cholesterol and phospholipids from cells by a multistep pathway that involves forming cell surface lipid domains, solubilizing these lipids by apolipoproteins, binding of apolipoproteins to ABCA1, and activating signaling processes. Here we used a mutational analysis approach to evaluate the relationship between these events. We prepared seven naturally occurring mutants and one artificial missense mutant of ABCA1 with varying degrees of impaired function, expressed them to similar levels as wild-type ABCA1 on the cell surface of BHK cells, and measured ABCA1-dependent lipid export, apolipoprotein A-I (apoA-I) binding, and signaling activities. Linear regression analyses showed that cholesterol and phospholipid efflux and cellular apoA-I binding correlated significantly with the ability of ABCA1 to form cell surface lipid domains. Lipid export and cellular apoA-I binding activities and formation of lipid domains also correlated with the amount of apoA-I that could be cross-linked to ABCA1. Moreover, each of these lipid export and apoA-I binding activities correlated with apoA-I-induced Janus kinase 2 (JAK2) activation. Thus, these missense mutations in ABCA1 impair lipid export, apoA-I binding, and apoA-I-stimulated JAK2 activities to similar extents, indicating that these processes are highly interactive components of a pathway that functions to export lipids from cells.
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No. Sentence Comment
50 We also generated an artificial mutation in the Walker A motif of NBD2 (A1950V) that corresponds to the A937V mutation in NBD1.
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ABCA1 p.Ala1950Val 18776170:50:72
status: NEW82 This activation was nearly abolished in cells expressing all mutants except two (W590S and A1950V), which are the same two mutants that have the highest ability to cross-link apoA-I (Fig. 2E).
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ABCA1 p.Ala1950Val 18776170:82:91
status: NEW93 The two most severe mutations, which reduced apoA-I-mediated lipid efflux to less than 20% of normal, were located in the first extracellular loop (Q597R) and the ATP binding site (A937V).
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ABCA1 p.Ala1950Val 18776170:93:72
status: NEW94 Interestingly, the equivalent mutation in the ATP binding site of NBD2 (A1950V) had only a modest impairment of ABCA1 function, suggesting that the ATP binding activity of NBD1 is more critical for function than that of NBD2 or that these mutations have different effects on protein conformation.
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ABCA1 p.Ala1950Val 18776170:94:72
status: NEW138 and A1950V, which also had near-normal apoA-I cross-linking activity.
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ABCA1 p.Ala1950Val 18776170:138:4
status: NEW137 and A1950V, which also had near-normal apoA-I cross-linking activity.
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ABCA1 p.Ala1950Val 18776170:137:4
status: NEW