1. Crystal structure of the human sterol transporter ABCG5/ABCG8.
- Author
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Lee JY, Kinch LN, Borek DM, Wang J, Wang J, Urbatsch IL, Xie XS, Grishin NV, Cohen JC, Otwinowski Z, Hobbs HH, and Rosenbaum DM
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 5, ATP Binding Cassette Transporter, Subfamily G, Member 8, 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 genetics, Lipoproteins metabolism, Models, Molecular, Molecular Sequence Data, Nucleotides, Phytosterols adverse effects, Phytosterols genetics, Protein Folding, Protein Multimerization, Protein Structure, Tertiary, ATP-Binding Cassette Transporters chemistry, Lipoproteins chemistry, Sterols metabolism
- 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.
- Published
- 2016
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