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. Here, 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:
-
- Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
- Texas Tech Univ. Health Sciences Center, Lubbock, TX (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; American Heart Association South Central Affiliate; American Heart Association Texas Affiliate; Welch Foundation; Packard Foundation; Howard Hughes Medical Inst.; National Inst. of Health
- OSTI Identifier:
- 1255303
- Grant/Contract Number:
- AC02-06CH11357; 0825285F; 0463130Y; I-1770; HL72304; P01-HL20948; GM094575; GM053163; GM117080; GM113050
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature (London)
- Additional Journal Information:
- Journal Name: Nature (London); Journal Volume: 533; Journal Issue: 7604; Journal ID: ISSN 0028-0836
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Transporters; X-ray crystallography
Citation Formats
Lee, Jyh-Yeuan, Kinch, Lisa N., Borek, Dominika M., Wang, Jin, Wang, Junmei, Urbatsch, Ina L., Xie, Xiao-Song, Grishin, Nikolai V., Cohen, Jonathan C., Otwinowski, Zbyszek, Hobbs, Helen H., and Rosenbaum, Daniel M. Crystal structure of the human sterol transporter ABCG5/ABCG8. United States: N. p., 2016.
Web. doi:10.1038/nature17666.
Lee, Jyh-Yeuan, Kinch, Lisa N., Borek, Dominika M., Wang, Jin, Wang, Junmei, Urbatsch, Ina L., Xie, Xiao-Song, Grishin, Nikolai V., Cohen, Jonathan C., Otwinowski, Zbyszek, Hobbs, Helen H., & Rosenbaum, Daniel M. Crystal structure of the human sterol transporter ABCG5/ABCG8. United States. https://doi.org/10.1038/nature17666
Lee, Jyh-Yeuan, Kinch, Lisa N., Borek, Dominika M., Wang, Jin, Wang, Junmei, Urbatsch, Ina L., Xie, Xiao-Song, Grishin, Nikolai V., Cohen, Jonathan C., Otwinowski, Zbyszek, Hobbs, Helen H., and Rosenbaum, Daniel M. Wed .
"Crystal structure of the human sterol transporter ABCG5/ABCG8". United States. https://doi.org/10.1038/nature17666. https://www.osti.gov/servlets/purl/1255303.
@article{osti_1255303,
title = {Crystal structure of the human sterol transporter ABCG5/ABCG8},
author = {Lee, Jyh-Yeuan and Kinch, Lisa N. and Borek, Dominika M. and Wang, Jin and Wang, Junmei and Urbatsch, Ina L. and Xie, Xiao-Song and Grishin, Nikolai V. and Cohen, Jonathan C. and Otwinowski, Zbyszek and Hobbs, Helen H. and Rosenbaum, Daniel M.},
abstractNote = {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. Here, 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.},
doi = {10.1038/nature17666},
journal = {Nature (London)},
number = 7604,
volume = 533,
place = {United States},
year = {Wed May 04 00:00:00 EDT 2016},
month = {Wed May 04 00:00:00 EDT 2016}
}
Web of Science
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Structural Biology and Structure–Function Relationships of Membrane Proteins
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Structural basis of small-molecule inhibition of human multidrug transporter ABCG2
text, January 2018
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Quantitative comparison of ABC membrane protein type I exporter structures in a standardized way
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Architecture of a channel-forming O-antigen polysaccharide ABC transporter
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Structure of the MacAB–TolC ABC-type tripartite multidrug efflux pump
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Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis
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A lipid gating mechanism for the channel-forming O antigen ABC transporter
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Expression and function of Abcg4 in the mouse blood-brain barrier: role in restricting the brain entry of amyloid-β peptide
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Expression of multidrug transporter P‐glycoprotein in Pichia pastoris affects the host's methanol metabolism
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3D structure of the transporter ABCG2—What's new?
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ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches
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Genes Potentially Associated with Familial Hypercholesterolemia
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