Distinct sites on ABCA1 control distinct steps required for cellular release of phospholipids.
The loss of ABCA1 function leads to Tangier dyslipidemia in humans and to a Tangier-like phenotype in mice, by impairing the transformation of nascent apolipoproteins into mature HDL particles. Mechanistically this ensues from the inability of cells to release membrane lipids and cholesterol. Whereas the ability of ABCA1 to promote phospholipid effluxes, surface binding of apolipoproteins and outward flip of membrane lipids has been documented, the relationship between this series of ABCA1-dependent events is still elusive. Here we provide evidence that i) lipid effluxes require both flip of membrane lipids and binding of apolipoproteins to the cell surface, ii) apolipoprotein A-I binding depends on structural determinants on ABCA1, and iii) phospholipid effluxes can be modulated by engineered mutations on the structural determinants identified on ABCA1.
Rigot
Véronique
V
Centre d'Immunologie de Marseille-Luminy, INSERM/CNRS/Université de la Méditerranée, Parc Scientifique de Luminy, Case 906, 13288 Marseille Cedex 09, France.
Hamon
Yannick
Y
Chambenoit
Olivier
O
Alibert
Mélanie
M
Duverger
Nicolas
N
Chimini
Giovanna
G
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D020125:Mutation, Missense; D010743:Phospholipids / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013631:Tangier Disease / Q000235:genetics
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D010743:Phospholipids