Structural snapshot of the cholesterol-transport ATP-binding cassette proteins

Abstract

The ATP-binding cassette (ABC) proteins play critical roles in maintaining lipid and sterol homeostasis in higher eukaryotes. In humans, several subfamily-A and -G members function as cholesterol transporters across the cellular membranes. Deficiencies of these ABC proteins can cause dyslipidemia that is associated with health conditions such as atherosclerosis, diabetes, fatty liver disease, and neurodegeneration. The physiological roles of ABC cholesterol transporters have been implicated in mediating cholesterol efflux for reverse cholesterol transport and in maintaining membrane integrity for cell survival. The precise role of these ABC transporters in cells remains elusive, and little is known about the sterol-transport mechanism. The membrane constituents of ABC transporters have been postulated to play a key role in determining the transport substrates and the translocation mechanisms via the transmembrane domains. Recent breakthroughs in determining high-resolution structures of the human sterol transporter ABCG5/G8 and its functional homologs have shed light on new structural features of ABC transporters, providing a more relevant framework for mechanistic analysis of cholesterol-transport ABC proteins. This minireview outlines what is known about ABCG cholesterol transporters, addresses key structural features in the putative sterol translocation pathway on the transmembrane domains, and concludes by proposing a mechanistic model of ABC cholesterol transporters.

Active cholesterol 20 years on

“…Cholesterol is translocated from plasma membranes to extracellular acceptors in the blood, bile and intestines by a family of ABC ATPases. While the structures and sterol binding motifs of some of the ABC transporters have been delineated, their molecular mechanisms and the pathways by which the sterol is exported have not been resolved in detail 107‐110 . One might imagine that these proteins simply pump excess active cholesterol from the plasma membrane; however, it appears in some cases that they utilize metabolic energy to activate cholesterol which then exits passively.…”

“…This heterodimer pumps excess cholesterol from the liver to the bile and ejects the toxic plant sterol, sitosterol, absorbed by the intestinal mucosa 109,126,127 Both cholesterol and bile acids stimulate the hydrolysis of ATP by ABCG5/8 in vitro. Presumably, these activities signify substrate‐ and acceptor‐level activation, respectively.…”

ABCG5/G8: a structural view to pathophysiology of the hepatobiliary cholesterol secretion

“…Lipid-transport membrane proteins have been shown to be essential for the translocation of sterols and phospholipids to maintain lipid homeostasis, cellular functions, and the structural integrity of mosaic lipid bilayers [7–9]. ATP-binding cassette (ABC) transporters are major sterol exporters responsible for both cholesterol efflux from peripheral cells and the elimination of excess cholesterol and dietary sterols [10,11]. ABC transporters comprise one of the largest evolutionarily conserved membrane protein families, which can transport a variety of substrates across the plasma membrane [12].…”

Genes Potentially Associated with Familial Hypercholesterolemia

“…Both proteins are composed of a magnesium-dependent ATP-binding domain at the N terminus (containing conserved peptide motifs Walker A and B) and a transmembrane domain including six transmembrane helices. The sixth transmembrane helix of ABCG8 carries a consensus sequence for the recognition of cholesterol; due to this sequence, only ABCG8 in the ABCG5/8 pair can serve as a sensor of the cholesterol level during its excretion [73].…”

“…On the basis of ABCG5-ABCG8 crystal structure, amino acid residues have been predicted whose substitutions disrupt the transport of cholesterol out of the cells; these are Arg389, Arg419, Asn437, Ile523, Arg550, Cys600, Gln604, and Met622 in ABCG5 and Thr400, Arg405, Leu501, Arg543, Leu572, Gly574, Gly575, and Leu596 in ABCG8 [73,76].…”