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Curr Biol

Title:		Selecting for Altered Substrate Specificity Reveals the Evolutionary Flexibility of ATP-Binding Cassette Transporters
Author(s):		Srikant S; Gaudet R; Murray AW;
Address:		"Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA. Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA. Electronic address: gaudet@mcb.harvard.edu. Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA. Electronic address: awm@mcb.harvard.edu"
Journal Title:		Curr Biol
Year:		2020
Volume:		20200326
Issue:		9
Page Number:		1689 - 1702
DOI:		10.1016/j.cub.2020.02.077
ISSN/ISBN:		1879-0445 (Electronic) 0960-9822 (Print) 0960-9822 (Linking)
Abstract:		"ATP-binding cassette (ABC) transporters are the largest family of ATP-hydrolyzing transporters, which import or export substrates across membranes, and have members in every sequenced genome. Structural studies and biochemistry highlight the contrast between the global structural similarity of homologous transporters and the enormous diversity of their substrates. How do ABC transporters evolve to carry such diverse molecules and what variations in their amino acid sequence alter their substrate selectivity? We mutagenized the transmembrane domains of a conserved fungal ABC transporter that exports a mating pheromone and selected for mutants that export a non-cognate pheromone. Mutations that alter export selectivity cover a region that is larger than expected for a localized substrate-binding site. Individual selected clones have multiple mutations, which have broadly additive contributions to specific transport activity. Our results suggest that multiple positions influence substrate selectivity, leading to alternative evolutionary paths toward selectivity for particular substrates and explaining the number and diversity of ABC transporters"
Keywords:		"ATP-Binding Cassette Transporters/genetics/*metabolism Ascomycota/*metabolism *Evolution, Molecular Fungal Proteins/genetics/metabolism Gene Expression Regulation, Fungal/physiology Mutation Protein Conformation Reproduction/physiology Substrate Specifici;"
Notes:		"MedlineSrikant, Sriram Gaudet, Rachelle Murray, Andrew W eng R01 GM043987/GM/NIGMS NIH HHS/ R01 GM120996/GM/NIGMS NIH HHS/ HHMI/Howard Hughes Medical Institute/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England 2020/03/30 Curr Biol. 2020 May 4; 30(9):1689-1702.e6. doi: 10.1016/j.cub.2020.02.077. Epub 2020 Mar 26"