Cytosolic N- and C-Termini of the Aspergillus nidulans FurE Transporter Contain Distinct Elements that Regulate by Long-Range Effects Function and Specificity |
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| Institution: | 1. Department of Biology, National and Kapodistrian University of Athens, Panepistimioupolis, Athens 15784, Greece;2. Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Athens 15771, Greece;1. ARC Centre of Excellence in Advanced Molecular Imaging, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia;2. Australian Synchrotron, 800 Blackburn Road, Clayton, Victoria 3168, Australia;3. School of Chemistry and Molecular Bioscience, University of Wollongong, and Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia;4. W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA;5. South East University-Monash Joint Institute, Institute of Life Sciences, Southeast University, Nanjing 210096, China;1. Department of Molecular Microbiology and Immunology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, 97239, OR, USA;2. NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21072, USA;1. Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India;2. Department of Mechanical Engineering, Jadavpur University, Kolkata, India;3. Department of Zoology, University of Calcutta, Kolkata, India |
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| Abstract: | FurE, a member of the NCS1 family, is an Aspergillus nidulans transporter specific for uracil, allantoin and uric acid. Recently, we showed that C- or N-terminally truncated FurE versions are blocked for endocytosis and surprisingly show modified substrate specificities. Bifluorescence complementation assays and genetic analyses supported the idea that C- and N-termini interact dynamically and through this interaction regulate selective substrate translocation. Here we functionally dissect and define distinct motifs crucial for endocytosis, transport activity, substrate specificity and folding, in both cytosolic termini of FurE. Subsequently, we obtain novel genetic and in silico evidence indicating that the molecular dynamics of specific N- and C-terminal regions exert long-range effects on the gating mechanism responsible for substrate selection, via pH-dependent interactions with other internal cytosolic loops and membrane lipids. Our work shows that expanded cytoplasmic termini, acquired through evolution mostly in eukaryotic transporters, provide novel specific functional roles. |
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