ABCMdb

PMID: 12738681

Wang N, Tall AR
Regulation and mechanisms of ATP-binding cassette transporter A1-mediated cellular cholesterol efflux.
Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1178-84. Epub 2003 May 8., [PubMed]

Sentences

No. Mutations Sentence Comment

41 ABCA1 p.Trp590Ser Importantly, many ABCA1 missense mutations causing Tangier disease have been identified in these loops.29 A functional test of these mutations in transfected cells revealed defects in apoA-I binding and cellular lipid efflux.27,28 Interestingly, one of the mutants, W590S, showed lipid efflux deficiency but moder- Figure 1. Login to comment 46 ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser Importantly, many ABCA1 missense mutations causing Tangier disease have been identified in these loops.29 A functional test of these mutations in transfected cells revealed defects in apoA-I binding and cellular lipid efflux.27,28 Interestingly, one of the mutants, W590S, showed lipid efflux deficiency but moder- Figure 1. Login to comment 51 ABCA1 p.Trp590Ser Together, these results also suggest that apoA-I binding requires an ABCA1 molecule assuming an optimal structural conformation that is maintained by a functional ATPase because cell-surface ABCA1 mutants with defective ATPase fail to bind apoA-I.23,32 The moderate increase in apoA-I binding to W590S may imply that dissociation of apoA-I from ABCA1 could be facilitated by lipid efflux to apolipoproteins bound to ABCA1 and is consistent with the earlier finding that ABCA1 binds apoA-I but not HDL3.7 Extrahepatic ABCA1 functions to promote cholesterol efflux from peripheral tissues to lipid-poor apolipoproteins that in turn deliver the lipid load back to liver for disposal, a process likely involving scavenger receptor BI, which has high affinity for lipid-rich HDLs but low affinity for lipid-poor apolipoproteins.33 Hepatic ABCA1 is likely involved in pre-beta HDL formation in liver, demonstrated by increased pre-beta HDL as well as more mature HDL levels in mice with adenovirus-mediated expression of ABCA1.34 Like scavenger receptor BI, ABCA1 binds not only apoA-I but also other apolipoproteins, including apoE.35 Thus, the antiatherogenic effect of apoE in vivo could be partially explained by lipid efflux from macrophage foam cells coordinated with ABCA1. Login to comment 73 ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser It may also cause conformational changes of ABCA1, as reported for ligand-induced conformational changes of other ABC transporters.48 Cholesterol efflux appears to have no effect on ABCA1 protein levels because HDL and cyclodextrin treatment promoted cholesterol efflux to an extent similar to or greater than that by apoA-I-mediated cholesterol efflux but failed to alter ABCA1 protein levels.31 Another mutation of ABCA1 that causes Tangier disease (W590S) has been shown to cause a moderate increase in apoA-I binding but defective lipid efflux.27 ApoA-I failed to increase ABCA1-W590S levels whereas calpeptin significantly increased ABCA1-W590S proteins, suggesting that apoA-I binding is not sufficient for ABCA1 stabilization.31 These results favor the hypothesis that apoA-I-mediated ABCA1 stabilization may result from a local change in membrane phospholipids that decreases the binding of a hydrophobic, glycine-rich sequence of the small calpain subunit.49 However, an equally valid interpretation is that apoA-I fails to bind the W590S mutant in the correct orientation and therefore the appropriate conformational change of ABCA1 required to decrease calpain proteolysis does not occur. Login to comment 78 ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser It may also cause conformational changes of ABCA1, as reported for ligand-induced conformational changes of other ABC transporters.48 Cholesterol efflux appears to have no effect on ABCA1 protein levels because HDL and cyclodextrin treatment promoted cholesterol efflux to an extent similar to or greater than that by apoA-I-mediated cholesterol efflux but failed to alter ABCA1 protein levels.31 Another mutation of ABCA1 that causes Tangier disease (W590S) has been shown to cause a moderate increase in apoA-I binding but defective lipid efflux.27 ApoA-I failed to increase ABCA1-W590S levels whereas calpeptin significantly increased ABCA1-W590S proteins, suggesting that apoA-I binding is not sufficient for ABCA1 stabilization.31 These results favor the hypothesis that apoA-I-mediated ABCA1 stabilization may result from a local change in membrane phospholipids that decreases the binding of a hydrophobic, glycine-rich sequence of the small calpain subunit.49 However, an equally valid interpretation is that apoA-I fails to bind the W590S mutant in the correct orientation and therefore the appropriate conformational change of ABCA1 required to decrease calpain proteolysis does not occur. Login to comment