title: Crystal structure of the human sterol transporter ABCG5/ABCG8.
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.
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Jyh-Yeuan
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Kinch
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Dominika M
authors.initials: DM
authors.lastname: Borek
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cecil &Ida Green Center for Molecular, Computational and Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
authors.forename: Ina L
authors.initials: IL
authors.lastname: Urbatsch
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Xie
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Grishin
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Zbyszek
authors.initials: Z
authors.lastname: Otwinowski
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rosenbaum
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics; D007410:Intestinal Diseases / Q000235:genetics; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics; D008074:Lipoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009711:Nucleotides; D010840:Phytosterols / Q000009:adverse effects / Q000235:genetics; D017510:Protein Folding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D013261:Sterols / Q000378:metabolism*
chemical_list: C416945:ABCG5 protein, human; C416946:ABCG8 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D008051:Lipid Bilayers; D008074:Lipoproteins; D009711:Nucleotides; D010840:Phytosterols; D013261:Sterols; D000251:Adenosine Triphosphatases