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Review
. 2022 Dec 28;24(1):484.
doi: 10.3390/ijms24010484.

Snapshots of ABCG1 and ABCG5/G8: A Sterol's Journey to Cross the Cellular Membranes

Fatemeh Rezaei  1 , Danny Farhat  1 , Gonca Gursu  1   2 , Sabrina Samnani  1   2 , Jyh-Yeuan Lee  1
Affiliations
Review

Snapshots of ABCG1 and ABCG5/G8: A Sterol's Journey to Cross the Cellular Membranes

Fatemeh Rezaei et al. Int J Mol Sci. .

Abstract

The subfamily-G ATP-binding cassette (ABCG) transporters play important roles in regulating cholesterol homeostasis. Recent progress in the structural data of ABCG1 and ABCG5/G8 disclose putative sterol binding sites that suggest the possible cholesterol translocation pathway. ABCG1 and ABCG5/G8 share high similarity in the overall molecular architecture, and both transporters appear to use several unique structural motifs to facilitate cholesterol transport along this pathway, including the phenylalanine highway and the hydrophobic valve. Interestingly, ABCG5/G8 is known to transport cholesterol and phytosterols, whereas ABCG1 seems to exclusively transport cholesterol. Ligand docking analysis indeed suggests a difference in recruiting sterol molecules to the known sterol-binding sites. Here, we further discuss how the different and shared structural features are relevant to their physiological functions, and finally provide our perspective on future studies in ABCG cholesterol transporters.

Keywords: ABCG1; ABCG5; ABCG8; RCT; TICE; sterol trasportation; structural motif.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Motifs and elements in ABCG1 and ABCG5/G8. (A) Stick illustration of structural motifs shown on the crystal structure of ABCG5/G8 (PDB ID: 8CUB). (a–i) In the extracellular region, hydrophobic valve residues are shown in pink; in the TMDs, phenylalanine highway, cholesterol-sensing motif, and polar relay are represented in green, red, and orange, respectively; in the NBDs, signature, Walker A, Walker B, and NPXDF motifs are illustrated in brick red, deep teal, deep olive, and yellow, respectively. * The tyrosin residue labelled in the polar relay and phenylalanine highway is common in these two motifs. (B) The same conserved motifs with comparable colors in the structure of an ABCG1 half transporter. The zoomed-in picture shows the involved residues appear to form a polar relay network on the TMD of an ABCG1 monomer. These residues are highly conserved in mammals (see Supplementary Materials). (C) The sequence alignment illustrates conserved residues of structural motifs shown in panels A and B in all ABCG subfamily members (colors are picked in accordance with the color code in panels (A,B)).
Figure 2
Figure 2
Cholesterol binding sites in the structures of ABCG1 and ABCG5/G8 proteins. (A) Comparison of cholesterol binding sites found on the determined structures of ABCG5/G8, as well as the involving residues. (a) This site (Site 3) was found in the crystal structure of ABCG5/G8 (PDB ID: 8CUB). (b,c). These binding sites (sites 1 and 2) were observed in the Cryo-EM structures of ABCG5/G8 (PDB ID: 7R8B and 7R8A, respectively). (B) Cartoon representation of ABCG1 in complex with two cholesterols forming a binding site. (a) Two cholesterol molecules colored in purple and green are from Cryo-EM structures of ABCG1, (PDB ID: 7FDV) and (PDB ID: 7R8D), respectively.
Figure 3
Figure 3
Molecular and cellular view of ABCG5/G8 and ABCG1 in their microenvironments. (A) Binding sites 1–3 of ABCG5/G8. Site 2 is on the back side of the protein. (B) Lipid and bile salt transporters of the canalicular membrane including their substrates and acceptor molecules, ABCG5/G8, ABCB11, ABCB4, NPC1L1 and NPC2 shown in cartoon. (PDB ID: 8CUB, 6LR0, 7NIV, 7DF8, 1NEP). (C) ABCG1 binding site and cholesterol trajectory towards protein and post efflux. (D) ABCG1 and lipid transporters expressed on macrophage: ABCA1, ABCG1 and SR-B1 (PDB ID: 7R8D, 5XYJ) (Alphafold).
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