Journal Article

ABCA1 is an extracellular phospholipid translocase

Jones, Martin K., Tang, Chongren, Davidson, W. Sean, Aller, Stephen G., Heinecke, Jay W., Segrest, Jere P., Song, Hyun D.

2022

Overview

Production of high density lipoprotein (HDL) requires ATP-binding cassette transporter A1 (ABCA1) to drive phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I. Here, we use simulations to show that domains of ABCA1 within the plasma membrane remove PL from the membrane’s outer leaflet. In our simulations, after the lipid diffuses into the interior of ABCA1’s outward-open cavity, PL extracted by the gateway passes through a ring-shaped domain, the annulus orifice, which forms the base of an elongated hydrophobic tunnel in the transporter’s extracellular domain. Engineered mutations in the gateway and annulus strongly inhibit lipid export by ABCA1 without affecting cell-surface expression levels. Our finding that ABCA1 extracts lipid from the outer face of the plasma membrane and forces it through its gateway and annulus into an elongated hydrophobic tunnel contrasts with the alternating access model, which proposes that ABCA1 flops PL substrate from the inner leaflet to the outer leaflet of the membrane. Consistent with our model, ABCA1 lacks the charged amino acid residues in the transmembrane domain found in the floppase members of the ABC transporter family. ATP-binding cassette transporter A1 (ABCA1) drives phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I, for the production of high density lipoprotein (HDL). Here, the authors use simulations to assess the mechanism of ABCA1 function and show that ABCA1 extracts lipid from the outer face of the plasma membrane.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/45/535/1267 / 631/45/612/1237 / 631/57/2266 / 631/57/2283 / ABC transporter / ABC transporters / ABCA1 protein / Amino acids / Annuli / Apolipoprotein A / Apolipoprotein A-I / Apolipoprotein A-I - metabolism / Apolipoproteins / ATP Binding Cassette Transporter 1 - genetics / ATP Binding Cassette Transporter 1 - metabolism / ATP-Binding Cassette Transporters - genetics / ATP-Binding Cassette Transporters - metabolism / ATP-binding protein / Binding / Cassettes / Cell Membrane - metabolism / Cell surface / Density / Domains / Elongation / High density lipoprotein / Humanities and Social Sciences / Hydrophobicity / Lipids / Lipoproteins, HDL - metabolism / Membranes / multidisciplinary / Mutation / Orifices / Phospholipids / Phospholipids - metabolism / Plasma / Protein Domains / Science / Science (multidisciplinary) / Simulation / Substrates / Translocase / Tunnels