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bioRxiv · 10.1101/2022.05.18.492512

Structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8

Farhat, D.·Rezaei, F.·Ristovski, M.·Yang, Y.·Stancescu, A.·Dzimkova, L.·Samnani, S.·Couture, J.-F.·Lee, J.-Y.
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Abstract

The ATP-binding cassette (ABC) sterol transporters are responsible for maintaining cholesterol homeostasis in mammals by participating in reverse cholesterol transport (RCT) or transintestinal cholesterol efflux (TICE). The heterodimeric ABCG5/G8 carries out selective sterol excretion, preventing the abnormal accumulation of plant sterols in human bodies, while homodimeric ABCG1 contributes to the biogenesis and metabolism of high-density lipoproteins. A sterol-binding site on ABCG5/G8 was proposed at the interface of the transmembrane domain and the core of lipid bilayers. In this study, we have determined the crystal structure of ABCG5/G8 in a cholesterol-bound state. The structure combined with amino acid sequence analysis shows that in the proximity of the sterol-binding site, a highly conserved phenylalanine array supports functional implications for ABCG cholesterol/sterol transporters. Lastly, in silico docking analysis of cholesterol and stigmasterol (a plant sterol) suggests sterol-binding selectivity on ABCG5/G8, but not ABCG1. Together, our results provide a structural basis for cholesterol binding on ABCG5/G8 and the sterol selectivity by ABCG transporters.

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Farhat, D., Rezaei, F., Ristovski, M., Yang, Y., Stancescu, A., Dzimkova, L., Samnani, S., Couture, J.-F., Lee, J.-Y.. 2022-05-18. Structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8. https://doi.org/10.1101/2022.05.18.492512

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