Abstract
The reverse cholesterol transport pathway is responsible for the maintenance of human cholesterol homeostasis, an imbalance of which usually leads to atherosclerosis. As a key component of this pathway, the ATP-binding cassette transporter ABCG1 forwards cellular cholesterol to the extracellular acceptor nascent high-density lipoprotein (HDL). Here, we report a 3.26-Å cryo-electron microscopy structure of cholesterol-bound ABCG1 in an inward-facing conformation, which represents a turnover condition upon ATP binding. Structural analyses combined with functional assays reveals that a cluster of conserved hydrophobic residues, in addition to two sphingomyelins, constitute a well-defined cholesterol-binding cavity. The exit of this cavity is closed by three pairs of conserved Phe residues, which constitute a hydrophobic path for the release of cholesterol in an acceptor concentration-dependent manner. Overall, we propose an ABCG1-driven cholesterol transport cycle initiated by sphingomyelin-assisted cholesterol recruitment and accomplished by the release of cholesterol to HDL.
Highlights
As a major element of the plasma membrane of mammalian cells, cholesterol plays a pivotal role in multiple biological processes, such as maintaining the membrane fluidity and biosynthesis of bile acids, steroid hormones, and vitamin D (Schade et al, 2020)
The excretion of cholesterol to the blood is first initiated by ABCA1, which transfers cellular cholesterol to lipid-free apolipoprotein A-I to form discoidal nascent high-density lipoprotein (HDL) in the extracellular milieu (Favari et al, 2009; Tarling and Edwards, 2012; Vaughan and Oram, 2005)
ABCG1 pumps out more cellular cholesterol to the nascent HDL, and this process gradually drives the remodeling and maturation of HDL, which is eventually released to the plasma (Gelissen et al, 2006; Vaughan and Oram, 2006)
Summary
As a major element of the plasma membrane of mammalian cells, cholesterol plays a pivotal role in multiple biological processes, such as maintaining the membrane fluidity and biosynthesis of bile acids, steroid hormones, and vitamin D (Schade et al, 2020). Cellular cholesterol homeostasis is subject to a finely tuned metabolic pathway Dysfunction of this pathway will cause atherosclerosis (Luo et al, 2020; Schaftenaar et al, 2016) and in most cases eventually lead to the development of coronary atherosclerotic heart disease, which is currently the leading cause of death in the world. Excess cholesterol could be pumped out to the intestinal lumen and bile ducts by the heterodimeric ABC transporter ABCG5/8 (Graf et al, 2003; Wang et al, 2015). These transmembrane proteins are needed to guarantee intracellular cholesterol homeostasis for cellular and systemic functions (Luo et al, 2020)
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