Molecular basis of cholesterol efflux via ABCG subfamily transporters

Proc Natl Acad Sci U S A. 2021 Aug 24;118(34):e2110483118. doi: 10.1073/pnas.2110483118.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • 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 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily G, Member 8 / chemistry
  • ATP Binding Cassette Transporter, Subfamily G, Member 8 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 8 / metabolism*
  • Adenosine Triphosphate / metabolism*
  • Binding Sites
  • Biological Transport
  • Cholesterol / metabolism*
  • Cryoelectron Microscopy
  • Humans
  • Protein Conformation

Substances

  • ABCG1 protein, human
  • ABCG8 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • Adenosine Triphosphate
  • Cholesterol