Crystal structure of the human sterol transporter ABCG5/ABCG8

Nature. 2016 May 26;533(7604):561-4. doi: 10.1038/nature17666. Epub 2016 May 4.

Abstract

ATP binding cassette (ABC) transporters play critical roles in maintaining sterol balance in higher eukaryotes. The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and intestines. Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Here we use crystallization in lipid bilayers to determine the X-ray structure of human G5G8 in a nucleotide-free state at 3.9 Å resolution, generating the first atomic model of an ABC sterol transporter. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. The G5G8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolaemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters / chemistry*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Adenosine Triphosphatases / metabolism
  • Amino Acid Sequence
  • Binding Sites
  • Biocatalysis
  • Crystallography, X-Ray
  • Humans
  • Hypercholesterolemia / genetics
  • Intestinal Diseases / genetics
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism
  • Lipid Metabolism, Inborn Errors / genetics
  • Lipoproteins / chemistry*
  • Lipoproteins / genetics
  • Lipoproteins / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Nucleotides
  • Phytosterols / adverse effects
  • Phytosterols / genetics
  • Protein Folding
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Sterols / metabolism*

Substances

  • ABCG5 protein, human
  • ABCG8 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters
  • Lipid Bilayers
  • Lipoproteins
  • Nucleotides
  • Phytosterols
  • Sterols
  • Adenosine Triphosphatases

Supplementary concepts

  • Sitosterolemia