Journal
CELL
Volume 169, Issue 7, Pages 1228-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.05.020
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Funding
- Ministry of Science and Technology of China [2015CB910101, 2016YFA0500402, 2014ZX09507003-006, 2016YFA0501100]
- National Natural Science Foundation of China [31621092, 31630017, 31611130036]
- Tsinghua-Peking Center for Life Sciences postdoctoral fellowship
- Advanced Innovation Fellowship from Beijing Advanced Innovation Center for Structural Biology
- International Early Career Scientist grant from the Howard Hughes Medical Institute
- endowed professorship from Bayer HealthCare
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ABCA1, an ATP-binding cassette (ABC) subfamily A exporter, mediates the cellular efflux of phospholipids and cholesterol to the extracellular acceptor apolipoprotein A-I (apoA-I) for generation of nascent high-density lipoprotein (HDL). Mutations of human ABCA1 are associated with Tangier disease and familial HDL deficiency. Here, we report the cryo-EM structure of human ABCA1 with nominal resolutions of 4.1 angstrom for the overall structure and 3.9 angstrom for the massive extracellular domain. The nucleotide-binding domains (NBDs) display a nucleotide-free state, while the two transmembrane domains (TMDs) contact each other through a narrow interface in the intracellular leaflet of the membrane. In addition to TMDs and NBDs, two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allows potential interpretation of their diverse pathogenic mechanisms. Structural-based analysis suggests a plausible lateral access'' mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm.
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