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      ABC transporter research: going strong 40 years on

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          Abstract

          In most organisms, ABC transporters constitute one of the largest families of membrane proteins. In humans, their functions are diverse and underpin numerous key physiological processes, as well as being causative factors in a number of clinically relevant pathologies. Advances in our understanding of these diseases have come about through combinations of genetic and protein biochemical investigations of these transporters and the power of in vitro and in vivo investigations is helping to develop genotype–phenotype understanding. However, the importance of ABC transporter research goes far beyond human biology; microbial ABC transporters are of great interest in terms of understanding virulence and drug resistance and industrial biotechnology researchers are exploring the potential of prokaryotic ABC exporters to increase the capacity of synthetic biology systems. Plant ABC transporters play important roles in transport of hormones, xenobiotics, metals and secondary metabolites, pathogen responses and numerous aspects of development, all of which are important in the global food security area. For 3 days in Chester, this Biochemical Society Focused Meeting brought together researchers with diverse experimental approaches and with different fundamental questions, all of which are linked by the commonality of ABC transporters.

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          Most cited references 60

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          Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.

          Overlapping complementary DNA clones were isolated from epithelial cell libraries with a genomic DNA segment containing a portion of the putative cystic fibrosis (CF) locus, which is on chromosome 7. Transcripts, approximately 6500 nucleotides in size, were detectable in the tissues affected in patients with CF. The predicted protein consists of two similar motifs, each with (i) a domain having properties consistent with membrane association and (ii) a domain believed to be involved in ATP (adenosine triphosphate) binding. A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients.
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            Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.

            The alpha- and beta-subunits of membrane-bound ATP synthase complex bind ATP and ADP: beta contributes to catalytic sites, and alpha may be involved in regulation of ATP synthase activity. The sequences of beta-subunits are highly conserved in Escherichia coli and bovine mitochondria. Also alpha and beta are weakly homologous to each other throughout most of their amino acid sequences, suggesting that they have common functions in catalysis. Related sequences in both alpha and beta and in other enzymes that bind ATP or ADP in catalysis, notably myosin, phosphofructokinase, and adenylate kinase, help to identify regions contributing to an adenine nucleotide binding fold in both ATP synthase subunits.
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              Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout.

              Genome-wide association studies (GWAS) have successfully identified common single nucleotide polymorphisms (SNPs) associated with a wide variety of complex diseases, but do not address gene function or establish causality of disease-associated SNPs. We recently used GWAS to identify SNPs in a genomic region on chromosome 4 that associate with serum urate levels and gout, a consequence of elevated urate levels. Here we show using functional assays that human ATP-binding cassette, subfamily G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter. We further show that native ABCG2 is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion. Introduction of the mutation Q141K encoded by the common SNP rs2231142 by site-directed mutagenesis resulted in 53% reduced urate transport rates compared to wild-type ABCG2 (P < 0.001). Data from a population-based study of 14,783 individuals support rs2231142 as the causal variant in the region and show highly significant associations with urate levels [whites: P = 10(-30), minor allele frequency (MAF) 0.11; blacks P = 10(-4), MAF 0.03] and gout (adjusted odds ratio 1.68 per risk allele, both races). Our data indicate that at least 10% of all gout cases in whites are attributable to this causal variant. With approximately 3 million US individuals suffering from often insufficiently treated gout, ABCG2 represents an attractive drug target. Our study completes the chain of evidence from association to causation and supports the common disease-common variant hypothesis in the etiology of gout.
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                Author and article information

                Journal
                Biochem Soc Trans
                Biochem. Soc. Trans
                ppbiost
                BST
                Biochemical Society Transactions
                Portland Press Ltd.
                0300-5127
                1470-8752
                9 October 2015
                1 October 2015
                : 43
                : 5 ( displayID: 5 )
                : 1033-1040
                Affiliations
                [* ]Biological Chemistry and Crop Protection Department, Rothamsted Research, Harpenden, AL5 2JQ, U.K.
                []School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, U.K.
                Author notes
                1Correspondence may be addressed to either author (email freddie.theodoulou@ 123456rothamsted.ac.uk or ian.kerr@ 123456nottingham.ac.uk ).
                Article
                BST20150139
                10.1042/BST20150139
                4652935
                26517919
                © 2015 Authors

                This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution Licence 3.0.

                Page count
                Figures: 2, Tables: 1, References: 62, Pages: 8
                Product
                Categories
                Biochemical Society Focused Meetings
                ATP binding cassette transporters: from mechanism to organism
                ATP binding cassette transporters: from mechanism to organism
                S7

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