2. Academic Validation
  3. Crystal structure of the human sterol transporter ABCG5/ABCG8

Crystal structure of the human sterol transporter ABCG5/ABCG8

  • Nature. 2016 May 26;533(7604):561-4. doi: 10.1038/nature17666.
Jyh-Yeuan Lee 1,  Lisa N Kinch 2 3 4,  Dominika M Borek 2 3,  Jin Wang 1,  Junmei Wang 5,  Ina L Urbatsch 6,  Xiao-Song Xie 1,  Nikolai V Grishin 2 3 4,  Jonathan C Cohen 1,  Zbyszek Otwinowski 2 3,  Helen H Hobbs 1 4,  Daniel M Rosenbaum 2 3
Affiliations

Affiliations

  • 1 Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
  • 2 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 4 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 5 Cecil &Ida Green Center for Molecular, Computational and Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 6 Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
PMID: 27144356 DOI: 10.1038/nature17666
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.

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