National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
米国
Welch Foundation
米国
Damon Runyon Cancer Research Foundation
米国
引用
ジャーナル: Proc Natl Acad Sci U S A / 年: 2021 タイトル: Molecular basis of cholesterol efflux via ABCG subfamily transporters. 著者: 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 / 要旨: 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 ...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.