Cholesterol sensing by the ABCG1 lipid transporter: Requirement of a CRAC motif in the final transmembrane domain

Biochimica Et Biophysica Acta
Laura J SharpeIngrid C Gelissen

Abstract

The ATP-binding cassette (ABC) transporter, ABCG1, is a lipid exporter involved in removal of cholesterol from cells that has been investigated for its role in foam cells formation and atherosclerosis. The mechanism by which ABC lipid transporters bind and recognise their substrates is currently unknown. In this study, we identify a critical region in the final transmembrane domain of ABCG1, which is essential for its export function and stabilisation by cholesterol, a post-translational regulatory mechanism that we have recently identified as dependent on protein ubiquitination. This transmembrane region contains several Cholesterol Recognition/interaction Amino acid Consensus (CRAC) motifs, and its inverse CARC motifs. Mutational analyses identify one CRAC motif in particular with Y667 at its core, that is especially important for transport activity to HDL as well as stability of the protein in the presence of cholesterol. In addition, we present a model of how cholesterol docks to this CRAC motif in an energetically favourable manner. This study identifies for the first time how ABCG1 can interact with cholesterol via a functional CRAC domain, which provides the first insight into the substrate-transporter interaction of an ...Continue Reading

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Citations

Mar 20, 2016·Chemistry and Physics of Lipids·Vicky HoweAndrew J Brown
May 25, 2016·Chemistry and Physics of Lipids·Arlene AlbertKathleen Boesze-Battaglia
Oct 4, 2016·Biochimica Et Biophysica Acta. Biomembranes·Jennifer NeumannUte A Hellmich
Sep 5, 2017·International Journal of Molecular Sciences·Lise M HardyWilfried Le Goff
Jul 31, 2018·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Bala M XavierJyh-Yeuan Lee
Sep 4, 2018·Journal of Lipids·Dmitry Y LitvinovAlexander D Dergunov
Sep 27, 2019·Pharmacological Reviews·Dongdong WangAtanas G Atanasov
Dec 7, 2018·The Journal of Membrane Biology·Alexander D DergunovDmitry Y Litvinov
Dec 15, 2020·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Ian D KerrIngrid C Gelissen
Jul 4, 2018·Pharmacology & Therapeutics·Lindsay C CzubaPeter W Swaan
Apr 4, 2021·International Journal of Molecular Sciences·Stanislav Kotlyarov
Apr 5, 2020·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Florina ZakanyZoltan Varga
Aug 27, 2021·Membranes·Miliça RistovskiJyh-Yeuan Lee
Aug 31, 2021·Journal of Molecular Biology·Liga SkardaKaspar P Locher

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