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      ABC transportome inventory of human pathogenic yeast Candida glabrata: Phylogenetic and expression analysis

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          Abstract

          ATP-binding cassette (ABC) is one of the two major superfamilies of transporters present across the evolutionary scale. ABC superfamily members came to prominence due to their ability to extrude broad spectrum of substrates and to confer multi drug resistance (MDR). Overexpression of some ABC transporters in clinical isolates of Candida species was attributed to the development of MDR phenotypes. Among Candida species, Candida glabrata is an emerging drug resistant species in human fungal infections. A comprehensive analysis of such proteins in C. glabrata is required to untangle their role not only in MDR but also in other biological processes. Bioinformatic analysis of proteins encoded by genome of human pathogenic yeast C. glabrata identified 25 putative ABC protein coding genes. On the basis of phylogenetic analysis, domain organization and nomenclature adopted by the Human Genome Organization (HUGO) scheme, these proteins were categorized into six subfamilies such as Pleiotropic Drug Resistance (PDR)/ABCG, Multi Drug Resistance (MDR)/ABCB, Multi Drug Resistance associated Protein (MRP)/ABCC, Adrenoleukodystrophy protein (ALDp)/ABCD, RNase L Inhibitor (RLI)/ABCE and Elongation Factor 3 (EF3)/ABCF. Among these, only 18 ABC proteins contained transmembrane domains (TMDs) and were grouped as membrane proteins, predominantly belonging to PDR, MDR, MRP, and ALDp subfamilies. A comparative phylogenetic analysis of these ABC proteins with other yeast species revealed their orthologous relationship and pointed towards their conserved functions. Quantitative real time PCR (qRT-PCR) analysis of putative membrane localized ABC protein encoding genes of C. glabrata confirmed their basal expression and showed variable transcriptional response towards antimycotic drugs. This study presents first comprehensive overview of ABC superfamily proteins of a human fungal pathogen C. glabrata, which is expected to provide an important platform for in depth analysis of their physiological relevance in cellular processes and drug resistance.

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          Plant ABC proteins--a unified nomenclature and updated inventory.

          The ABC superfamily comprises both membrane-bound transporters and soluble proteins involved in a broad range of processes, many of which are of considerable agricultural, biotechnological and medical potential. Completion of the Arabidopsis and rice genome sequences has revealed a particularly large and diverse complement of plant ABC proteins in comparison with other organisms. Forward and reverse genetics, together with heterologous expression, have uncovered many novel roles for plant ABC proteins, but this progress has been accompanied by a confusing proliferation of names for plant ABC genes and their products. A consolidated nomenclature will provide much-needed clarity and a framework for future research.
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            Structure and mechanism of ABC transporters

            All living organisms depend on primary and secondary membrane transport for the supply of external nutrients and removal or sequestration of unwanted (toxic) compounds. Due to the chemical diversity of cellular molecules, it comes as no surprise that a significant part of the proteome is dedicated to the active transport of cargo across the plasma membrane or the membranes of subcellular organelles. Transport against a chemical gradient can be driven by, for example, the free energy change associated with ATP hydrolysis (primary transport), or facilitated by the potential energy of the chemical gradient of another molecule (secondary transport). Primary transporters include the rotary motor ATPases (F-, A-, and V-ATPases), P-type ATPases and a large family of integral membrane proteins referred to as “ABC” (ATP binding cassette) transporters. ABC transporters are widespread in all forms of life and are characterized by two nucleotide-binding domains (NBD) and two transmembrane domains (TMDs). ATP hydrolysis on the NBD drives conformational changes in the TMD, resulting in alternating access from inside and outside of the cell for unidirectional transport across the lipid bilayer. Common to all ABC transporters is a signature sequence or motif, LSGGQ, that is involved in nucleotide binding. Both importing and exporting ABC transporters are found in bacteria, whereas the majority of eukaryotic family members function in the direction of export. Recent progress with the X-ray crystal structure determination of a variety of bacterial and eukaryotic ABC transporters has helped to advance our understanding of the ATP hydrolysis-driven transport mechanism but has also illustrated the large structural and functional diversity within the family.
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              The human ATP-binding cassette (ABC) transporter superfamily.

              The transport of specific molecules across lipid membranes is an essential function of all living organisms and a large number of specific transporters have evolved to carry out this function. The largest transporter gene family is the ATP-binding cassette (ABC) transporter superfamily. These proteins translocate a wide variety of substrates including sugars, amino acids, metal ions, peptides, and proteins, and a large number of hydrophobic compounds and metabolites across extra- and intracellular membranes. ABC genes are essential for many processes in the cell, and mutations in these genes cause or contribute to several human genetic disorders including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response. Characterization of eukaryotic genomes has allowed the complete identification of all the ABC genes in the yeast Saccharomyces cerevisiae, Drosophila, and C. elegans genomes. To date, there are 48 characterized human ABC genes. The genes can be divided into seven distinct subfamilies, based on organization of domains and amino acid homology. Many ABC genes play a role in the maintenance of the lipid bilayer and in the transport of fatty acids and sterols within the body. Here, we review the current knowledge of the human ABC genes, their role in inherited disease, and understanding of the topology of these genes within the membrane.

                Author and article information

                Contributors
                Role: Data curationRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Software
                Role: MethodologyRole: SoftwareRole: Writing – review & editing
                Role: Methodology
                Role: Methodology
                Role: SoftwareRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 August 2018
                2018
                : 13
                : 8
                : e0202993
                Affiliations
                [1 ] Yeast Biofuel Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
                [2 ] Amity Institute of Integrative Science and Health, Amity University Gurgaon, Haryana, India
                [3 ] School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
                Vallabhbhai Patel Chest Institute, INDIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-0271-4958
                http://orcid.org/0000-0002-6794-4001
                Article
                PONE-D-18-08135
                10.1371/journal.pone.0202993
                6112666
                30153284
                c9c85f7b-29fb-4bd3-a223-e1671b1f1572
                © 2018 Kumari et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 March 2018
                : 12 August 2018
                Page count
                Figures: 6, Tables: 2, Pages: 21
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001407, Department of Biotechnology, Ministry of Science and Technology;
                Award ID: BT/01/CEIB/10/III/02, BT/PR7392/MED/29/652/2012, BT/PR14117/BRB/10/1420/2015
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001407, Department of Biotechnology, Ministry of Science and Technology;
                Award ID: BT/PR10684/PBD/26/403/2013, BT/PB/Centre/03/2011
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001409, Department of Science and Technology, Ministry of Science and Technology;
                Award ID: SR/S2/RJN-07/2012
                Award Recipient :
                The work has been supported in parts by grants to R.P. from the Department of Biotechnology DBT [No. BT/01/CEIB/10/III/02], DBT [No. BT/PR7392/MED/29/652/2012] and DBT [No. BT/PR14117/BRB/10/1420/2015] and in parts by grants to N.A.G. by DST Ramanujan Fellowship grant [SR/S2/RJN-07/2012], DBT grants [No. BT/PR10684/PBD/26/403/2013] and DBT [No. BT/PB/Centre/03/2011]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Research and Analysis Methods
                Experimental Organism Systems
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                Saccharomyces Cerevisiae
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