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

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.

Automated summary

The subfamily-G ATP-binding cassette (ABCG) transporters are important for regulating cholesterol homeostasis. Recent structural data of ABCG1 and ABCG5/G8 reveal potential sterol binding sites and a proposed cholesterol translocation pathway. Both ABCG1 and ABCG5/G8 share similar overall molecular architecture and use unique structural motifs, such as the phenylalanine highway and hydrophobic valve, to facilitate cholesterol transport. However, ABCG1 exclusively transports cholesterol while ABCG5/G8 can transport both cholesterol and phytosterols. Ligand docking analysis suggests differences in recruiting sterol molecules to their binding sites. This article discusses the relevance of different and shared structural features to their physiological functions and provides perspectives for future studies on ABCG cholesterol transporters.