Molecular basis of cholesterol efflux via ABCG subfamily transporters

Yingyuan Sun, Jin Wang, Tao Long, Xiaofeng Qi, Linda Donnelly, Nadia Elghobashi-Meinhardt, Leticia Esparza, Jonathan C. Cohen, Xiao Song Xie, Helen H. Hobbs, Xiaochun Li

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Article numbere2110483118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number34
StatePublished - Aug 24 2021


  • ABCG1
  • ABCG5
  • ABCG8
  • Plant sterol
  • Sitosterolemia

ASJC Scopus subject areas

  • General


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