ESPEYB19 14. Science and Medicine Basics of human biology (3 abstracts)
14.3. Structure and transport mechanism of the human cholesterol transporter ABCG1
Da Xu , Yanyan Li , Fengrui Yang , Cai-Rong Sun , Jinheng Pan , Liang Wang , Zhi-Peng Chen , Shu-Cheng Fang , Xuebiao Yao , Wen-Tao Hou , Cong-Zhao Zhou & Yuxing Chen
Cell Rep. 2022 Jan 25;38(4):110298. doi: 10.1016/j.celrep.2022.110298
Brief Summary: This study describes the cryo-EM structure of human ATP Binding Cassette Subfamily G Member 1 (ABCG1) in complex with cholesterol. The authors propose a structural mechanism whereby cholesterol is recruited from cell membranes by sphingomyelin and loaded on nascent HDL particles.
ABCG1 mediates the addition of cholesterol to nascent HDL particles as part of the reverse cholesterol transport destined to excess cholesterol catabolism and excretion by the liver. This role of ABCG1 is mostly studied in macrophages, where ABCG1 inactivation results in intracellular accumulation of neutral lipids and phospholipids that facilitates the formation of foam cells and atherosclerotic plaques. These authors report the first cryo-EM structure of human ABCG1 at a resolution of 3.26 A �. They combine in vitroand functional assays to propose a model in which ABCG1 recruits 2 cholesterol molecules, each shuttled by a sphingomyelin moiety. Following activation by ATP, cholesterol is then released by the transport protein to acceptor HDL particles through a hydrophobic channel made of 3 pairs of Phenylalanine residues.
This study offers the first structural glance into a key component of the reverse cholesterol pathway. Therefore, it holds strong promise for shedding further light on the mechanisms that regulate physiological extrusion of excess cholesterol from macrophages and prevent their transformation into foam cells and atherosclerotic events.
Volume 19
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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