ABCA1 p.Leu2251Ala
| Predicted by SNAP2: | A: D (53%), C: N (57%), D: D (59%), E: D (59%), F: N (82%), G: D (53%), H: N (53%), I: N (78%), K: N (57%), M: N (78%), N: D (53%), P: N (57%), Q: N (53%), R: N (53%), S: N (61%), T: N (53%), V: N (82%), W: D (53%), Y: N (61%), |
| 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] Liver X receptor beta (LXRbeta) interacts directly... J Biol Chem. 2011 Jun 3;286(22):20117-24. Epub 2011 Apr 20. Hozoji-Inada M, Munehira Y, Nagao K, Kioka N, Ueda K
Liver X receptor beta (LXRbeta) interacts directly with ATP-binding cassette A1 (ABCA1) to promote high density lipoprotein formation during acute cholesterol accumulation.
J Biol Chem. 2011 Jun 3;286(22):20117-24. Epub 2011 Apr 20., [PMID:21507939]
Abstract [show]
Cells have evolved multiple mechanisms for maintaining cholesterol homeostasis, and, among these, ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux is highly regulated at the transcriptional level through the activity of the nuclear receptor liver X receptor (LXR). Here, we show that in addition to its well defined role in transcription, LXRbeta directly binds to the C-terminal region ((2247)LTSFL(2251)) of ABCA1 to mediate its post-translational regulation. In the absence of cholesterol accumulation in the macrophage-like cell line THP-1, the ABCA1-LXRbeta complex stably localizes to the plasma membrane, but apolipoprotein A-I (apoA-I) binding or cholesterol efflux does not occur. Exogenously added LXR ligands, which mimic cholesterol accumulation, cause LXRbeta to dissociate from ABCA1, thus freeing ABCA1 for apoA-I binding and subsequent cholesterol efflux. Photoaffinity labeling experiments with 8-azido-[alpha-(32)P]ATP showed that the interaction of LXRbeta with ABCA1 inhibits ATP binding by ABCA1. This is the first study to show that a protein-protein interaction with the endogenous protein suppresses the function of ABC proteins by inhibiting ATP binding. LXRbeta can cause a post-translational response by binding directly to ABCA1, as well as a transcriptional response, to maintain cholesterol homeostasis.
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No. Sentence Comment
90 However, mutation of Leu2247 and Leu2251 to alanine abrogated the co-precipitation of LXRbeta despite comparable levels of expression among these mutants and WT ABCA1.
X
ABCA1 p.Leu2251Ala 21507939:90:33
status: NEW108 HEK293 cells stably expressing FLAG-tagged LXRbeta were transfected with HA-tagged WT ABCA1 L2247A mutant or L2251A mutant.
X
ABCA1 p.Leu2251Ala 21507939:108:109
status: NEW113 When the mutant constructs were expressed in HEK293 cells, L2247A or L2251A substitution did not affect the surface expression of ABCA1, but LXRbeta no longer co-localized with ABCA1 (Fig. 2).
X
ABCA1 p.Leu2251Ala 21507939:113:69
status: NEW120 Interestingly, apoA-I bound to cells expressing L2247A or L2251A mutant ABCA1 even when LXRbeta was co-expressed.
X
ABCA1 p.Leu2251Ala 21507939:120:58
status: NEW122 When ABCA1-L2247A, ABCA1-L2251A, or ABCA1-L2247A/L2251A was expressed alone, cholesterol efflux to apoA-I was comparable with cells expressing WT ABCA1 in the absence or presence of TO901317 (black bars and empty bars, respectively, in Fig. 3B).
X
ABCA1 p.Leu2251Ala 21507939:122:25
status: NEWX
ABCA1 p.Leu2251Ala 21507939:122:49
status: NEW126 Co-expression of LXRbeta doubled the plasma membrane levels of WT ABCA1 as shown previously (16), but surface levels of the mutants (L2247A, L2251A, and L2247/L2251A) were not affected by LXRbeta expression (Fig. 3C).
X
ABCA1 p.Leu2251Ala 21507939:126:141
status: NEWX
ABCA1 p.Leu2251Ala 21507939:126:159
status: NEW149 ABCA1-L2247A/L2251A double mutant was labeled as efficiently as WT ABCA1 (lane 9), but this was not inhibited by LXRbeta co-expression (lanes 11 and 12), suggesting that the interaction of LXRbeta with ABCA1 via Leu2247 and Leu2251 prevents tight ATP binding.
X
ABCA1 p.Leu2251Ala 21507939:149:13
status: NEW89 However, mutation of Leu2247 and Leu2251 to alanine abrogated the co-precipitation of LXRbeta despite comparable levels of expression among these mutants and WT ABCA1.
X
ABCA1 p.Leu2251Ala 21507939:89:33
status: NEW107 HEK293 cells stably expressing FLAG-tagged LXRbeta were transfected with HA-tagged WT ABCA1 L2247A mutant or L2251A mutant.
X
ABCA1 p.Leu2251Ala 21507939:107:109
status: NEW112 When the mutant constructs were expressed in HEK293 cells, L2247A or L2251A substitution did not affect the surface expression of ABCA1, but LXRbeta no longer co-localized with ABCA1 (Fig. 2).
X
ABCA1 p.Leu2251Ala 21507939:112:69
status: NEW119 Interestingly, apoA-I bound to cells expressing L2247A or L2251A mutant ABCA1 even when LXRbeta was co-expressed.
X
ABCA1 p.Leu2251Ala 21507939:119:58
status: NEW121 When ABCA1-L2247A, ABCA1-L2251A, or ABCA1-L2247A/L2251A was expressed alone, cholesterol efflux to apoA-I was comparable with cells expressing WT ABCA1 in the absence or presence of TO901317 (black bars and empty bars, respectively, in Fig. 3B).
X
ABCA1 p.Leu2251Ala 21507939:121:25
status: NEWX
ABCA1 p.Leu2251Ala 21507939:121:49
status: NEW125 Co-expression of LXRbeta doubled the plasma membrane levels of WT ABCA1 as shown previously (16), but surface levels of the mutants (L2247A, L2251A, and L2247/L2251A) were not affected by LXRbeta expression (Fig. 3C).
X
ABCA1 p.Leu2251Ala 21507939:125:141
status: NEWX
ABCA1 p.Leu2251Ala 21507939:125:159
status: NEW148 ABCA1-L2247A/L2251A double mutant was labeled as efficiently as WT ABCA1 (lane 9), but this was not inhibited by LXRbeta co-expression (lanes 11 and 12), suggesting that the interaction of LXRbeta with ABCA1 via Leu2247 and Leu2251 prevents tight ATP binding.
X
ABCA1 p.Leu2251Ala 21507939:148:13
status: NEW