Cell Reports (Jan 2022)

Structure and transport mechanism of the human cholesterol transporter ABCG1

  • Da Xu,
  • Yanyan Li,
  • Fengrui Yang,
  • Cai-Rong Sun,
  • Jinheng Pan,
  • Liang Wang,
  • Zhi-Peng Chen,
  • Shu-Cheng Fang,
  • Xuebiao Yao,
  • Wen-Tao Hou,
  • Cong-Zhao Zhou,
  • Yuxing Chen

Journal volume & issue
Vol. 38, no. 4
p. 110298

Abstract

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Summary: The reverse cholesterol transport pathway is responsible for the maintenance of human cholesterol homeostasis, an imbalance of which usually leads to atherosclerosis. As a key component of this pathway, the ATP-binding cassette transporter ABCG1 forwards cellular cholesterol to the extracellular acceptor nascent high-density lipoprotein (HDL). Here, we report a 3.26-Å cryo-electron microscopy structure of cholesterol-bound ABCG1 in an inward-facing conformation, which represents a turnover condition upon ATP binding. Structural analyses combined with functional assays reveals that a cluster of conserved hydrophobic residues, in addition to two sphingomyelins, constitute a well-defined cholesterol-binding cavity. The exit of this cavity is closed by three pairs of conserved Phe residues, which constitute a hydrophobic path for the release of cholesterol in an acceptor concentration-dependent manner. Overall, we propose an ABCG1-driven cholesterol transport cycle initiated by sphingomyelin-assisted cholesterol recruitment and accomplished by the release of cholesterol to HDL.

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