@article{a979e658d48f469b80696b3e9d4aaa98,
title = "Structure of the Human Lipid Exporter ABCA1",
abstract = "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 {\AA} for the overall structure and 3.9 {\AA} 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.",
keywords = "ABC transporters, ABCA1, Tangier disease, cryo-EM structure, familial HDL deficiency, lipid exporter, nascent HDL formation, reverse cholesterol transport",
author = "Hongwu Qian and Xin Zhao and Pingping Cao and Jianlin Lei and Nieng Yan and Xin Gong",
note = "Funding Information: We thank Xiaomei Li and Xiaomin Li for technical support during EM image acquisition. We thank Qiang Zhou for critical discussions. We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We thank the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of China National Center for Protein Sciences Beijing) and the “Explorer 100” cluster system of Tsinghua National Laboratory for Information Science and Technology. This work was supported by funds from the Ministry of Science and Technology of China (2015CB910101, 2016YFA0500402, 2014ZX09507003-006, and 2016YFA0501100) and the National Natural Science Foundation of China (projects 31621092, 31630017, and 31611130036). X.G. was supported by the Tsinghua-Peking Center for Life Sciences postdoctoral fellowship and Advanced Innovation Fellowship from Beijing Advanced Innovation Center for Structural Biology. N.Y. was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute and an endowed professorship from Bayer HealthCare. Funding Information: We thank Xiaomei Li and Xiaomin Li for technical support during EM image acquisition. We thank Qiang Zhou for critical discussions. We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We thank the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of China National Center for Protein Sciences Beijing) and the ?Explorer 100? cluster system of Tsinghua National Laboratory for Information Science and Technology. This work was supported by funds from the Ministry of Science and Technology of China (2015CB910101, 2016YFA0500402, 2014ZX09507003-006, and 2016YFA0501100) and the National Natural Science Foundation of China (projects 31621092, 31630017, and 31611130036). X.G. was supported by the Tsinghua-Peking Center for Life Sciences postdoctoral fellowship and Advanced Innovation Fellowship from Beijing Advanced Innovation Center for Structural Biology. N.Y. was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute and an endowed professorship from Bayer HealthCare. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jun,
day = "15",
doi = "10.1016/j.cell.2017.05.020",
language = "English (US)",
volume = "169",
pages = "1228--1239.e10",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "7",
}