Open AccessCrystal structure of the human sterol transporter ABCG5/ABCG8
Author(s) -
Jyh-Yeuan Lee,
Lisa N. Kinch,
Dominika Borek,
Jin Wang,
Junmei Wang,
Ina L. Urbatsch,
Xiao Song Xie,
N.V. Grishin,
Jonathan C. Cohen,
Zbyszek Otwinowski,
Helen H. Hobbs,
Daniel M. Rosenbaum
Publication year - 2016
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/nature17666
Subject(s) - atp binding cassette transporter , sterol , transporter , biochemistry , sterol regulatory element binding protein , biology , transmembrane domain , transmembrane protein , atpase , microbiology and biotechnology , cholesterol , chemistry , gene , enzyme , receptor
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.