@article{44f407572b9a470e99d0b7947056640d,
title = "Molecular basis of cholesterol efflux via ABCG subfamily transporters",
abstract = "The ABCG1 homodimer (G1) and ABCG5–ABCG8 heterodimer (G5G8), two members of the adenosine triphosphate (ATP)–binding cassette (ABC) transporter G family, are required for maintenance of cellular cholesterol levels. G5G8 mediates secretion of neutral sterols into bile and the gut lumen, whereas G1 transports cholesterol from macrophages to high-density lipoproteins (HDLs). The mechanisms used by G5G8 and G1 to recognize and export sterols remain unclear. Here, we report cryoelectron microscopy (cryo-EM) structures of human G5G8 in sterol-bound and human G1 in cholesterol- and ATP-bound states. Both transporters have a sterol-binding site that is accessible from the cytosolic leaflet. A second site is present midway through the transmembrane domains of G5G8. The Walker A motif of G8 adopts a unique conformation that accounts for the marked asymmetry in ATPase activities between the two nucleotide-binding sites of G5G8. These structures, along with functional validation studies, provide a mechanistic framework for understanding cholesterol efflux via ABC transporters.",
keywords = "ABCG1, ABCG5, ABCG8, Plant sterol, Sitosterolemia",
author = "Yingyuan Sun and Jin Wang and Tao Long and Xiaofeng Qi and Linda Donnelly and Nadia Elghobashi-Meinhardt and Leticia Esparza and Cohen, {Jonathan C.} and Xie, {Xiao Song} and Hobbs, {Helen H.} and Xiaochun Li",
note = "Funding Information: The data were collected at the Howard Hughes Medical Institute Janelia Research Campus and the University of Texas Southwestern Medical Center Cryo-EM Facility (funded in part by Cancer Prevention & Research Institute of Texas Core Facility Support Award RP170644). We thank D. Stoddard, R. Yan, and Z. Yu for assistance in data collection and M. Brown, E. Debler, R. DeBose-Boyd, J. Goldstein, and P. Schmiege for discussion during manuscript preparation. We also thank J. Lee for preparing the antigen that was used to generate the monoclonal antibodies, F. Xu for measuring sterol lipids, and C. Zhao for genotyping. This work was supported by NIH Grants P01 HL020948 (to H.H.H. and X.L.), R01 GM134700 (to X.L.), and R01 HL072304 (to H.H.H.) and the Welch Foundation (Grant I-1957) (to X.L.). X.Q. is the recipient of a DDBrown Fellowship of the Life Sciences Research Foundation. X.L. is a Damon Runyon-Rachleff Innovator supported by the Damon Runyon Cancer Research Foundation (Grant DRR-53S-19). Funding Information: ACKNOWLEDGMENTS. The data were collected at the Howard Hughes Medical Institute Janelia Research Campus and the University of Texas South-western Medical Center Cryo-EM Facility (funded in part by Cancer Prevention & Research Institute of Texas Core Facility Support Award RP170644). We thank D. Stoddard, R. Yan, and Z. Yu for assistance in data collection and M. Brown, E. Debler, R. DeBose-Boyd, J. Goldstein, and P. Schmiege for discussion during manuscript preparation. We also thank J. Lee for preparing the antigen that was used to generate the monoclonal antibodies, F. Xu for measuring sterol lipids, and C. Zhao for genotyping. This work was supported by NIH Grants P01 HL020948 (to H.H.H. and X.L.), R01 GM134700 (to X.L.), and R01 HL072304 (to H.H.H.) and the Welch Foundation (Grant I-1957) (to X.L.). X.Q. is the recipient of a DDBrown Fellowship of the Life Sciences Research Foundation. X.L. is a Damon Runyon-Rachleff Innovator supported by the Damon Runyon Cancer Research Foundation (Grant DRR-53S-19). Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = aug,
day = "24",
doi = "10.1073/pnas.2110483118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "34",
}