ABCA1 p.Tyr1767Asp
| Predicted by SNAP2: | A: D (80%), C: D (85%), D: D (91%), E: D (91%), F: D (71%), G: D (91%), H: D (91%), I: D (85%), K: D (95%), L: D (85%), M: D (91%), N: D (91%), P: D (91%), Q: D (85%), R: D (95%), S: D (85%), T: D (85%), V: D (85%), W: D (91%), |
| Predicted by PROVEAN: | A: D, 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, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Functional rescue of mutant ABCA1 proteins by sodi... J Lipid Res. 2013 Jan;54(1):55-62. doi: 10.1194/jlr.M027193. Epub 2012 Oct 20. Sorrenson B, Suetani RJ, Williams MJ, Bickley VM, George PM, Jones GT, McCormick SP
Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate.
J Lipid Res. 2013 Jan;54(1):55-62. doi: 10.1194/jlr.M027193. Epub 2012 Oct 20., [PMID:23087442]
Abstract [show]
Mutations in the ATP-binding cassette transporter A1 (ABCA1) are a major cause of decreased HDL cholesterol (HDL-C), which infers an increased risk of cardiovascular disease (CVD). Many ABCA1 mutants show impaired localization to the plasma membrane. The aim of this study was to investigate whether the chemical chaperone, sodium 4-phenylbutyrate (4-PBA) could improve cellular localization and function of ABCA1 mutants. Nine different ABCA1 mutants (p.A594T, p.I659V, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, p.A2028V, p.Q2239N) expressed in HEK293 cells, displaying different degrees of mislocalization to the plasma membrane and discrete impacts on cholesterol efflux, were subject to treatment with 4-PBA. Treatment restored localization to the plasma membrane and increased cholesterol efflux function for the majority of mutants. Treatment with 4-PBA also increased ABCA1 protein expression in all transfected cell lines. In fibroblast cells obtained from low HDL-C subjects expressing two of the ABCA1 mutants (p.R1068H and p.N1800H), 4-PBA increased cholesterol efflux without any increase in ABCA1 expression. Our study is the first to investigate the effect of the chemical chaperone, 4-PBA on ABCA1 and shows that it is capable of restoring plasma membrane localization and enhancing the cholesterol efflux function of mutant ABCA1s both in vitro and ex vivo. These results suggest 4-PBA may warrant further investigation as a potential therapy for increasing cholesterol efflux and HDL-C levels.
Comments [show]
None has been submitted yet.
No. Sentence Comment
16 Nine different ABCA1 mutants (p.A594T, p.I659V, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, p.A2028V, p.Q2239N) expressed in HEK293 cells, displaying different degrees of mislocalization to the plasma membrane and discrete impacts on cholesterol efflux, were subject to treatment with 4-PBA.
X
ABCA1 p.Tyr1767Asp 23087442:16:70
status: NEW54 We identified a further three novel mutations, p.A594T, p.Y1767D, and p.Q2239N, and these were also included in this study. We hypothesized that efflux function would be improved for mutants that are dysfunctional as a result of protein mislocation.
X
ABCA1 p.Tyr1767Asp 23087442:54:58
status: NEW73 Both media were RESULTS ABCA1 mutants with impaired localization have reduced cholesterol efflux function We identified three novel ABCA1 variants, p.A594T, p.Y1767D, and p.Q2239N, in heterozygote form in three individuals with HDL-C levels of 0.61, 0.17, and 0.37 mmol/L, respectively.
X
ABCA1 p.Tyr1767Asp 23087442:73:162
status: NEW74 The individual heterozygote for p.Y1767D was also heterozygote for the p.N1800H ABCA1 mutation.
X
ABCA1 p.Tyr1767Asp 23087442:74:34
status: NEW77 Investigation of the six uncharacterized mutations in transfected HEK293 cells showed the p.A594T, p.I659V, p.Y1767D, p.R2004K, and p.A2028V mutants to have various degrees of mislocalization (Fig. 2A).
X
ABCA1 p.Tyr1767Asp 23087442:77:110
status: NEW79 Areas of mislocalized ABCA1-GFP are indicated by arrows in Fig. 2A with the p.Y1767D and R2004K mutants being the most affected.
X
ABCA1 p.Tyr1767Asp 23087442:79:78
status: NEW80 The mislocalization of mutant ABCA1s was associated with a reduced cholesterol efflux function compared with wild-type-GFP ABCA1 (Fig. 2B) with the p.Y1767D mutant being the most affected (30.3% the efflux of wild-type).
X
ABCA1 p.Tyr1767Asp 23087442:80:150
status: NEW109 Upon 4-PBA treatment, efflux function was significantly increased relative to the untreated level for the p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, and p.A2028V mutants (Fig. 3B).
X
ABCA1 p.Tyr1767Asp 23087442:109:128
status: NEW112 Treatment with 4-PBA induced a significant increase in colocalization for the p.A594T, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, and p.R2004K mutants. Treatment with 4-PBA did not affect the colocalization of the wild-type ABCA1-GFP protein (supplementary Fig. II).
X
ABCA1 p.Tyr1767Asp 23087442:112:109
status: NEW125 mislocated mutants, p.Y1767D, and p.N1800H, showed a restored efflux function that was equivalent to wild-type untreated cells.
X
ABCA1 p.Tyr1767Asp 23087442:125:22
status: NEW164 For example, the p.Y1767D mutant showed a much enhanced localization and dramatic increase in cholesterol efflux after 4-PBA treatment whereas the efflux function for the p.R1068H mutant remained low despite showing a similar enhancement in localization.
X
ABCA1 p.Tyr1767Asp 23087442:164:19
status: NEW