Structure and transport mechanism of the human cholesterol transporter ABCG1

Cell Rep. 2022 Jan 25;38(4):110298. doi: 10.1016/j.celrep.2022.110298.


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.

Keywords: ABC transporter; atherosclerosis; cholesterol; cryo-EM; human ABCG1; reverse cholesterol transport; sphingomyelin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / chemistry*
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / ultrastructure*
  • Cholesterol / metabolism
  • Cryoelectron Microscopy
  • Humans
  • Sphingomyelins / metabolism


  • ABCG1 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • Sphingomyelins
  • Cholesterol