Research Article
Structure of the Human Cholesterol Transporter ABCG1

https://doi.org/10.1016/j.jmb.2021.167218Get rights and content
Under a Creative Commons license
open access

Highlights

  • ABCG1 transports cholesterol as part of reverse cholesterol transport pathway.

  • Cryo-EM structure of human ABCG1 in an inward open conformation.

  • Comparison with ABCG2 reveals basis for substrate specificity differences.

  • First insight into ABCG1-mediated cholesterol recognition.

Abstract

ABCG1 is an ATP binding cassette (ABC) transporter that removes excess cholesterol from peripheral tissues. Despite its role in preventing lipid accumulation and the development of cardiovascular and metabolic disease, the mechanism underpinning ABCG1-mediated cholesterol transport is unknown. Here we report a cryo-EM structure of human ABCG1 at 4 Å resolution in an inward-open state, featuring sterol-like density in the binding cavity. Structural comparison with the multidrug transporter ABCG2 and the sterol transporter ABCG5/G8 reveals the basis of mechanistic differences and distinct substrate specificity. Benzamil and taurocholate inhibited the ATPase activity of liposome-reconstituted ABCG1, whereas the ABCG2 inhibitor Ko143 did not. Based on the structural insights into ABCG1, we propose a mechanism for ABCG1-mediated cholesterol transport.

Keywords

ABC transporter
reverse cholesterol transport
single particle cryo-EM
HDL
ATP hydrolysis

Abbreviations used

ABC
ATP-binding cassette
cryo-EM
cryo-electron
NBD
nucleotide binding domain
TMD
transmembrane domains
RCT
reverse cholesterol transport
CHS
cholesteryl hemisuccinate
GDN
glycodiosgenin

Cited by (0)