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

Autor:	Sharpe LJ; Faculty of Pharmacy, The University of Sydney, Sydney NSW 2006, Australia; School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia., Rao G; Faculty of Pharmacy, The University of Sydney, Sydney NSW 2006, Australia., Jones PM; School of Medical and Molecular Biosciences, University of Technology Sydney, Sydney NSW 2007, Australia., Glancey E; Faculty of Pharmacy, The University of Sydney, Sydney NSW 2006, Australia., Aleidi SM; Faculty of Pharmacy, The University of Sydney, Sydney NSW 2006, Australia., George AM; School of Medical and Molecular Biosciences, University of Technology Sydney, Sydney NSW 2007, Australia., Brown AJ; School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia., Gelissen IC; Faculty of Pharmacy, The University of Sydney, Sydney NSW 2006, Australia. Electronic address: ingrid.gelissen@sydney.edu.au.
Jazyk:	angličtina
Zdroj:	Biochimica et biophysica acta [Biochim Biophys Acta] 2015 Jul; Vol. 1851 (7), pp. 956-64. Date of Electronic Publication: 2015 Feb 27.
DOI:	10.1016/j.bbalip.2015.02.016
Abstrakt:	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 ABC lipid exporter. (Copyright © 2015 Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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