TY - JOUR AU - Hamdoun, A. AU - Hellmich, U.A. AU - Szakács, Gergely AU - Kuchler, K. TI - The incredible diversity of structures and functions of ABC transporters JF - FEBS LETTERS J2 - FEBS LETT VL - 595 PY - 2021 IS - 6 SP - 671 EP - 674 PG - 4 SN - 0014-5793 DO - 10.1002/1873-3468.14061 UR - https://m2.mtmt.hu/api/publication/31953886 ID - 31953886 N1 - Scripps Institution of Oceanography, UC San DiegoCA, United States Institute of Organic Chemistry and Macromolecular Chemistry, Cluster of Excellence 'Balance of the Microverse', Friedrich-Schiller-University Jena, Germany Institute of Enzymology, Research Centre of Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary Institute of Cancer Research, Medical University of Vienna, Austria Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University Vienna, Austria Export Date: 7 April 2021 CODEN: FEBLA Correspondence Address: Hamdoun, A.; Scripps Institution of Oceanography, United States; email: ahamdoun@ucsd.edu Correspondence Address: Hellmich, U.A.; Institute of Organic Chemistry and Macromolecular Chemistry, Germany; email: ute.hellmich@uni-jena.de Correspondence Address: Szakacs, G.; Institute of Enzymology, Hungary; email: gergely-szakacs@meduniwien.ac.at Correspondence Address: Szakacs, G.; Institute of Cancer Research, Austria; email: gergely-szakacs@meduniwien.ac.at Scripps Institution of Oceanography, UC San DiegoCA, United States Institute of Organic Chemistry and Macromolecular Chemistry, Cluster of Excellence 'Balance of the Microverse', Friedrich-Schiller-University Jena, Germany Institute of Enzymology, Research Centre of Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary Institute of Cancer Research, Medical University of Vienna, Austria Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University Vienna, Austria Export Date: 13 August 2021 CODEN: FEBLA Correspondence Address: Hamdoun, A.; Scripps Institution of Oceanography, United States; email: ahamdoun@ucsd.edu Correspondence Address: Hellmich, U.A.; Institute of Organic Chemistry and Macromolecular Chemistry, Germany; email: ute.hellmich@uni-jena.de Correspondence Address: Szakacs, G.; Institute of Enzymology, Hungary; email: gergely-szakacs@meduniwien.ac.at Correspondence Address: Szakacs, G.; Institute of Cancer Research, Austria; email: gergely-szakacs@meduniwien.ac.at LA - English DB - MTMT ER - TY - JOUR AU - Nagy, Tamás AU - Tóth, Ágota AU - Telbisz, Ágnes Mária AU - Sarkadi, Balázs AU - Tordai, Hedvig AU - Tordai, Attila AU - Hegedűs, Tamás TI - The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations JF - CELLULAR AND MOLECULAR LIFE SCIENCES J2 - CELL MOL LIFE SCI VL - 78 PY - 2021 IS - 5 SP - 2329 EP - 2339 PG - 11 SN - 1420-682X DO - 10.1007/s00018-020-03651-3 UR - https://m2.mtmt.hu/api/publication/31623716 ID - 31623716 AB - Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions. © 2020, The Author(s). LA - English DB - MTMT ER - TY - JOUR AU - Farkas, Bianka Vivien AU - Tordai, Hedvig AU - Padányi, Rita AU - Tordai, Attila AU - Gera, János AU - Paragi, Gábor AU - Hegedűs, Tamás TI - Discovering the chloride pathway in the CFTR channel JF - CELLULAR AND MOLECULAR LIFE SCIENCES J2 - CELL MOL LIFE SCI VL - 77 PY - 2020 IS - 4 SP - 765 EP - 778 PG - 12 SN - 1420-682X DO - 10.1007/s00018-019-03211-4 UR - https://m2.mtmt.hu/api/publication/30745347 ID - 30745347 N1 - Funding Agency and Grant Number: Semmelweis Egyetem [Sci_Innov18] Funding Source: Medline; Cystic Fibrosis Foundation (US) [HEGEDU18I0] Funding Source: Medline; Nemzeti Kutatasi, Fejlesztesi es Innovacios Hivatal (HU) [K127961, K111678] Funding Source: Medline Cited By :2 Export Date: 31 August 2021 CODEN: CMLSF Correspondence Address: Hegedűs, T.; Department of Biophysics and Radiation Biology, Hungary; email: hegedus@hegelab.org LA - English DB - MTMT ER - TY - JOUR AU - Sarkadi, Balázs AU - Homolya, László AU - Hegedűs, Tamás TI - The ABCG2/BCRP transporter and its variants - from structure to pathology JF - FEBS LETTERS J2 - FEBS LETT VL - 594 PY - 2020 IS - 23 SP - 4012 EP - 4034 PG - 23 SN - 0014-5793 DO - 10.1002/1873-3468.13947 UR - https://m2.mtmt.hu/api/publication/31634543 ID - 31634543 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office [K 127961, K 128123] Funding text: This work has been supported by National Research, Development and Innovation Office (grant numbers: K 127961 to TH and K 128123 to LH. The authors thank M~at~e Homolya for his help in graphics. Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Cited By :6 Export Date: 2 June 2021 CODEN: FEBLA Correspondence Address: Sarkadi, B.; Institute of Enzymology, Hungary; email: sarkadi@biomembrane.hu Correspondence Address: Sarkadi, B.; Department of Biophysics and Radiation Biology, Hungary; email: sarkadi@biomembrane.hu Funding Agency and Grant Number: National Research, Development and Innovation OfficeNational Research, Development & Innovation Office (NRDIO) - Hungary [K 127961, K 128123] Funding text: This work has been supported by National Research, Development and Innovation Office (grant numbers: K 127961 to TH and K 128123 to LH. The authors thank M~at~e Homolya for his help in graphics. Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Cited By :7 Export Date: 28 August 2021 CODEN: FEBLA Correspondence Address: Sarkadi, B.; Institute of Enzymology, Hungary; email: sarkadi@biomembrane.hu Correspondence Address: Sarkadi, B.; Department of Biophysics and Radiation Biology, Hungary; email: sarkadi@biomembrane.hu Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Cited By :7 Export Date: 31 August 2021 CODEN: FEBLA Correspondence Address: Sarkadi, B.; Institute of Enzymology, Hungary; email: sarkadi@biomembrane.hu Correspondence Address: Sarkadi, B.; Department of Biophysics and Radiation Biology, Hungary; email: sarkadi@biomembrane.hu Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Cited By :7 Export Date: 8 September 2021 CODEN: FEBLA Correspondence Address: Sarkadi, B.; Institute of Enzymology, Hungary; email: sarkadi@biomembrane.hu Correspondence Address: Sarkadi, B.; Department of Biophysics and Radiation Biology, Hungary; email: sarkadi@biomembrane.hu AB - The ABCG2 protein has a key role in the transport of a wide range of structurally dissimilar endo- and xenobiotics in the human body, especially in the tissue barriers and the metabolizing or secreting organs. The human ABCG2 gene harbors a high number of polymorphisms and mutations, which may significantly modulate its expression and function. Recent high-resolution structural data, complemented with molecular dynamic simulations, may significantly help to understand intramolecular movements and substrate handling, as well as the effects of mutations on the membrane transporter function of ABCG2. As reviewed here, structural alterations may result not only in direct alterations in drug binding and transporter activity, but also in improper folding or problems in the carefully regulated process of trafficking, including vesicular transport, endocytosis, recycling, and degradation. Here, we also review the clinical importance of altered ABCG2 expression and function in general drug metabolism, cancer multidrug resistance, and impaired uric acid excretion, leading to gout. LA - English DB - MTMT ER - TY - JOUR AU - Thomas, C. AU - Aller, S.G. AU - Beis, K. AU - Carpenter, E.P. AU - Chang, G. AU - Chen, L. AU - Dassa, E. AU - Dean, M. AU - Duong, Van Hoa F. AU - Ekiert, D. AU - Ford, R. AU - Gaudet, R. AU - Gong, X. AU - Holland, I.B. AU - Huang, Y. AU - Kahne, D.K. AU - Kato, H. AU - Koronakis, V. AU - Koth, C.M. AU - Lee, Y. AU - Lewinson, O. AU - Lill, R. AU - Martinoia, E. AU - Murakami, S. AU - Pinkett, H.W. AU - Poolman, B. AU - Rosenbaum, D. AU - Sarkadi, Balázs AU - Schmitt, L. AU - Schneider, E. AU - Shi, Y. AU - Shyng, S.-L. AU - Slotboom, D.J. AU - Tajkhorshid, E. AU - Tieleman, D.P. AU - Ueda, K. AU - Váradi, András AU - Wen, P.-C. AU - Yan, N. AU - Zhang, P. AU - Zheng, H. AU - Zimmer, J. AU - Tampé, R. TI - Structural and functional diversity calls for a new classification of ABC transporters JF - FEBS LETTERS J2 - FEBS LETT VL - 594 PY - 2020 IS - 23 SP - 3767 EP - 3775 PG - 9 SN - 0014-5793 DO - 10.1002/1873-3468.13935 UR - https://m2.mtmt.hu/api/publication/31664473 ID - 31664473 N1 - Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Germany Department of Pharmacology and Toxicology, University of Alabama at BirminghamAL, United States Department of Life Sciences, Imperial College London, London South Kensington, United Kingdom Rutherford Appleton Laboratory, Research Complex at Harwell, Didcot, United Kingdom Structural Genomics Consortium, University of Oxford, United Kingdom Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, United States State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China Institut Pasteur, Paris Cedex 15, France Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, United States Department of Biochemistry and Molecular Biology, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada Department of Cell Biology and Department of Microbiology, New York University School of MedicineNY, United States Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States Department of Biology, Southern University of Science and Technology, Shenzhen, China Institute for Integrative Biology of the Cell (I2BC), Université Paris-Sud, Orsay, France National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Japan Department of Pathology, University of Cambridge, United Kingdom Structural Biology, Genentech Inc., South San Francisco, CA, United States Division of Integrative Bioscience and Biotechnology, POSTECH, Pohang, South Korea Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel Institut für Zytobiologie, Philipps-Universität Marburg, Germany Department of Plant and Microbial Biology, University Zurich, Switzerland International Research Centre for Environmental Membrane Biology, Foshan University, Foshan, China Department of Life Science, Tokyo Institute of Technology, Yokohama, Japan Department of Molecular Biosciences, Northwestern University, Evanston, IL, United States Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Netherlands Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, United States Institute of Enzymology, Research Center for Natural Sciences (RCNS), Budapest, Hungary Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany Department of Biology/Microbial Physiology, Humboldt-University of Berlin, Germany Institute of Biology, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, China Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, United States Department of Biochemistry, Center for Biophysics and Quantitative Biology, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-ChampaignIL, United States Department of Biological Sciences and Centre for Molecular Simulation, University of CalgaryAB, Canada Institute for Integrated Cell-Material Sciences (WPI-iCeMS), KUIAS, Kyoto University, Japan Department of Molecular Biology, Princeton UniversityNJ, United States National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, United States Export Date: 17 November 2020 CODEN: FEBLA Correspondence Address: Thomas, C.; Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Institute of Biochemistry, Biocenter, Goethe University FrankfurtGermany; email: c.thomas@em.uni-frankfurt.de Funding details: Canada Research Chairs Funding details: Wellcome Trust, WT, LI 415/5, 101828/Z/13/Z Funding details: National Institutes of Health, NIH, MR/N000994/1 Funding details: Medical Research Council, MRC, MR/N020103/1 Funding details: Deutsche Forschungsgemeinschaft, DFG, SFB 807, TA157/12‐1 Funding text 1: K.B. acknowledges support by a grant of the Medical Research Council (MR/N020103/1). M.D. is supported in part by the Intramural Program of the NIH. V.K. acknowledges support by the Medical Research Council (MR/N000994/1) and Wellcome Trust (101828/Z/13/Z). R.L. acknowledges generous financial support from German Research Foundation (LI 415/5). D.P.T. is supported in part by the Canada Research Chairs program. This work was supported by the German Research Foundation (SFB 807 and TA157/12‐1 (Reinhart Koselleck Award Program) to R.T.). Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Germany Department of Pharmacology and Toxicology, University of Alabama at BirminghamAL, United States Department of Life Sciences, Imperial College London, London South Kensington, United Kingdom Rutherford Appleton Laboratory, Research Complex at Harwell, Didcot, United Kingdom Structural Genomics Consortium, University of Oxford, United Kingdom Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, United States State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China Institut Pasteur, Paris Cedex 15, France Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, United States Department of Biochemistry and Molecular Biology, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada Department of Cell Biology and Department of Microbiology, New York University School of MedicineNY, United States Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States Department of Biology, Southern University of Science and Technology, Shenzhen, China Institute for Integrative Biology of the Cell (I2BC), Université Paris-Sud, Orsay, France National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Japan Department of Pathology, University of Cambridge, United Kingdom Structural Biology, Genentech Inc., South San Francisco, CA, United States Division of Integrative Bioscience and Biotechnology, POSTECH, Pohang, South Korea Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel Institut für Zytobiologie, Philipps-Universität Marburg, Germany Department of Plant and Microbial Biology, University Zurich, Switzerland International Research Centre for Environmental Membrane Biology, Foshan University, Foshan, China Department of Life Science, Tokyo Institute of Technology, Yokohama, Japan Department of Molecular Biosciences, Northwestern University, Evanston, IL, United States Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Netherlands Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, United States Institute of Enzymology, Research Center for Natural Sciences (RCNS), Budapest, Hungary Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany Department of Biology/Microbial Physiology, Humboldt-University of Berlin, Germany Institute of Biology, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, China Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, United States Department of Biochemistry, Center for Biophysics and Quantitative Biology, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-ChampaignIL, United States Department of Biological Sciences and Centre for Molecular Simulation, University of CalgaryAB, Canada Institute for Integrated Cell-Material Sciences (WPI-iCeMS), KUIAS, Kyoto University, Japan Department of Molecular Biology, Princeton UniversityNJ, United States National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, United States Cited By :3 Export Date: 5 February 2021 CODEN: FEBLA Correspondence Address: Thomas, C.; Institute of Biochemistry, Germany; email: c.thomas@em.uni-frankfurt.de Correspondence Address: Tampé, R.; Institute of Biochemistry, Germany; email: tampe@em.uni-frankfurt.de Funding details: Canada Research Chairs Funding details: Wellcome Trust, WT, LI 415/5, 101828/Z/13/Z Funding details: National Institutes of Health, NIH, MR/N000994/1 Funding details: Medical Research Council, MRC, MR/N020103/1 Funding details: Deutsche Forschungsgemeinschaft, DFG, SFB 807, TA157/12‐1 Funding text 1: K.B. acknowledges support by a grant of the Medical Research Council (MR/N020103/1). M.D. is supported in part by the Intramural Program of the NIH. V.K. acknowledges support by the Medical Research Council (MR/N000994/1) and Wellcome Trust (101828/Z/13/Z). R.L. acknowledges generous financial support from German Research Foundation (LI 415/5). D.P.T. is supported in part by the Canada Research Chairs program. This work was supported by the German Research Foundation (SFB 807 and TA157/12‐1 (Reinhart Koselleck Award Program) to R.T.). Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Germany Department of Pharmacology and Toxicology, University of Alabama at BirminghamAL, United States Department of Life Sciences, Imperial College London, London South Kensington, United Kingdom Rutherford Appleton Laboratory, Research Complex at Harwell, Didcot, United Kingdom Structural Genomics Consortium, University of Oxford, United Kingdom Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, United States State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China Institut Pasteur, Paris Cedex 15, France Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, United States Department of Biochemistry and Molecular Biology, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada Department of Cell Biology and Department of Microbiology, New York University School of MedicineNY, United States Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States Department of Biology, Southern University of Science and Technology, Shenzhen, China Institute for Integrative Biology of the Cell (I2BC), Université Paris-Sud, Orsay, France National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Japan Department of Pathology, University of Cambridge, United Kingdom Structural Biology, Genentech Inc., South San Francisco, CA, United States Division of Integrative Bioscience and Biotechnology, POSTECH, Pohang, South Korea Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel Institut für Zytobiologie, Philipps-Universität Marburg, Germany Department of Plant and Microbial Biology, University Zurich, Switzerland International Research Centre for Environmental Membrane Biology, Foshan University, Foshan, China Department of Life Science, Tokyo Institute of Technology, Yokohama, Japan Department of Molecular Biosciences, Northwestern University, Evanston, IL, United States Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Netherlands Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, United States Institute of Enzymology, Research Center for Natural Sciences (RCNS), Budapest, Hungary Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany Department of Biology/Microbial Physiology, Humboldt-University of Berlin, Germany Institute of Biology, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, China Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, United States Department of Biochemistry, Center for Biophysics and Quantitative Biology, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-ChampaignIL, United States Department of Biological Sciences and Centre for Molecular Simulation, University of CalgaryAB, Canada Institute for Integrated Cell-Material Sciences (WPI-iCeMS), KUIAS, Kyoto University, Japan Department of Molecular Biology, Princeton UniversityNJ, United States National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, United States Cited By :10 Export Date: 1 April 2021 CODEN: FEBLA Correspondence Address: Thomas, C.; Institute of Biochemistry, Germany; email: c.thomas@em.uni-frankfurt.de Correspondence Address: Tampé, R.; Institute of Biochemistry, Germany; email: tampe@em.uni-frankfurt.de Funding details: National Institutes of Health, NIH, MR/N000994/1 Funding details: Wellcome Trust, WT, 101828/Z/13/Z, LI 415/5 Funding details: Medical Research Council, MRC, MR/N020103/1 Funding details: Deutsche Forschungsgemeinschaft, DFG, SFB 807, TA157/12‐1 Funding details: Canada Research Chairs Funding text 1: K.B. acknowledges support by a grant of the Medical Research Council (MR/N020103/1). M.D. is supported in part by the Intramural Program of the NIH. V.K. acknowledges support by the Medical Research Council (MR/N000994/1) and Wellcome Trust (101828/Z/13/Z). R.L. acknowledges generous financial support from German Research Foundation (LI 415/5). D.P.T. is supported in part by the Canada Research Chairs program. This work was supported by the German Research Foundation (SFB 807 and TA157/12‐1 (Reinhart Koselleck Award Program) to R.T.). Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Germany Department of Pharmacology and Toxicology, University of Alabama at BirminghamAL, United States Department of Life Sciences, Imperial College London, London South Kensington, United Kingdom Rutherford Appleton Laboratory, Research Complex at Harwell, Didcot, United Kingdom Structural Genomics Consortium, University of Oxford, United Kingdom Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, United States State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China Institut Pasteur, Paris Cedex 15, France Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, United States Department of Biochemistry and Molecular Biology, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada Department of Cell Biology and Department of Microbiology, New York University School of MedicineNY, United States Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States Department of Biology, Southern University of Science and Technology, Shenzhen, China Institute for Integrative Biology of the Cell (I2BC), Université Paris-Sud, Orsay, France National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Japan Department of Pathology, University of Cambridge, United Kingdom Structural Biology, Genentech Inc., South San Francisco, CA, United States Division of Integrative Bioscience and Biotechnology, POSTECH, Pohang, South Korea Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel Institut für Zytobiologie, Philipps-Universität Marburg, Germany Department of Plant and Microbial Biology, University Zurich, Switzerland International Research Centre for Environmental Membrane Biology, Foshan University, Foshan, China Department of Life Science, Tokyo Institute of Technology, Yokohama, Japan Department of Molecular Biosciences, Northwestern University, Evanston, IL, United States Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Netherlands Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, United States Institute of Enzymology, Research Center for Natural Sciences (RCNS), Budapest, Hungary Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany Department of Biology/Microbial Physiology, Humboldt-University of Berlin, Germany Institute of Biology, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, China Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, United States Department of Biochemistry, Center for Biophysics and Quantitative Biology, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-ChampaignIL, United States Department of Biological Sciences and Centre for Molecular Simulation, University of CalgaryAB, Canada Institute for Integrated Cell-Material Sciences (WPI-iCeMS), KUIAS, Kyoto University, Japan Department of Molecular Biology, Princeton UniversityNJ, United States National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, United States Cited By :10 Export Date: 3 May 2021 CODEN: FEBLA Correspondence Address: Thomas, C.; Institute of Biochemistry, Germany; email: c.thomas@em.uni-frankfurt.de Correspondence Address: Tampé, R.; Institute of Biochemistry, Germany; email: tampe@em.uni-frankfurt.de Funding details: National Institutes of Health, NIH, MR/N000994/1 Funding details: Wellcome Trust, WT, 101828/Z/13/Z, LI 415/5 Funding details: Medical Research Council, MRC, MR/N020103/1 Funding details: Deutsche Forschungsgemeinschaft, DFG, SFB 807, TA157/12‐1 Funding details: Canada Research Chairs Funding text 1: K.B. acknowledges support by a grant of the Medical Research Council (MR/N020103/1). M.D. is supported in part by the Intramural Program of the NIH. V.K. acknowledges support by the Medical Research Council (MR/N000994/1) and Wellcome Trust (101828/Z/13/Z). R.L. acknowledges generous financial support from German Research Foundation (LI 415/5). D.P.T. is supported in part by the Canada Research Chairs program. This work was supported by the German Research Foundation (SFB 807 and TA157/12‐1 (Reinhart Koselleck Award Program) to R.T.). Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Germany Department of Pharmacology and Toxicology, University of Alabama at BirminghamAL, United States Department of Life Sciences, Imperial College London, London South Kensington, United Kingdom Rutherford Appleton Laboratory, Research Complex at Harwell, Didcot, United Kingdom Structural Genomics Consortium, University of Oxford, United Kingdom Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, United States State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China Institut Pasteur, Paris Cedex 15, France Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, United States Department of Biochemistry and Molecular Biology, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada Department of Cell Biology and Department of Microbiology, New York University School of MedicineNY, United States Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States Department of Biology, Southern University of Science and Technology, Shenzhen, China Institute for Integrative Biology of the Cell (I2BC), Université Paris-Sud, Orsay, France National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Japan Department of Pathology, University of Cambridge, United Kingdom Structural Biology, Genentech Inc., South San Francisco, CA, United States Division of Integrative Bioscience and Biotechnology, POSTECH, Pohang, South Korea Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel Institut für Zytobiologie, Philipps-Universität Marburg, Germany Department of Plant and Microbial Biology, University Zurich, Switzerland International Research Centre for Environmental Membrane Biology, Foshan University, Foshan, China Department of Life Science, Tokyo Institute of Technology, Yokohama, Japan Department of Molecular Biosciences, Northwestern University, Evanston, IL, United States Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Netherlands Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, United States Institute of Enzymology, Research Center for Natural Sciences (RCNS), Budapest, Hungary Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany Department of Biology/Microbial Physiology, Humboldt-University of Berlin, Germany Institute of Biology, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, China Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, United States Department of Biochemistry, Center for Biophysics and Quantitative Biology, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-ChampaignIL, United States Department of Biological Sciences and Centre for Molecular Simulation, University of CalgaryAB, Canada Institute for Integrated Cell-Material Sciences (WPI-iCeMS), KUIAS, Kyoto University, Japan Department of Molecular Biology, Princeton UniversityNJ, United States National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, United States Cited By :20 Export Date: 30 July 2021 CODEN: FEBLA Correspondence Address: Thomas, C.; Institute of Biochemistry, Germany; email: c.thomas@em.uni-frankfurt.de Correspondence Address: Tampé, R.; Institute of Biochemistry, Germany; email: tampe@em.uni-frankfurt.de Chemicals/CAS: ATP-Binding Cassette Transporters Funding details: National Institutes of Health, NIH, MR/N000994/1 Funding details: Wellcome Trust, WT, 101828/Z/13/Z, LI 415/5 Funding details: Medical Research Council, MRC, MR/N020103/1 Funding details: Deutsche Forschungsgemeinschaft, DFG, SFB 807, TA157/12‐1 Funding details: Canada Research Chairs Funding text 1: K.B. acknowledges support by a grant of the Medical Research Council (MR/N020103/1). M.D. is supported in part by the Intramural Program of the NIH. V.K. acknowledges support by the Medical Research Council (MR/N000994/1) and Wellcome Trust (101828/Z/13/Z). R.L. acknowledges generous financial support from German Research Foundation (LI 415/5). D.P.T. is supported in part by the Canada Research Chairs program. This work was supported by the German Research Foundation (SFB 807 and TA157/12‐1 (Reinhart Koselleck Award Program) to R.T.). Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Germany Department of Pharmacology and Toxicology, University of Alabama at BirminghamAL, United States Department of Life Sciences, Imperial College London, London South Kensington, United Kingdom Rutherford Appleton Laboratory, Research Complex at Harwell, Didcot, United Kingdom Structural Genomics Consortium, University of Oxford, United Kingdom Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, United States State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China Institut Pasteur, Paris Cedex 15, France Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, United States Department of Biochemistry and Molecular Biology, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada Department of Cell Biology and Department of Microbiology, New York University School of MedicineNY, United States Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States Department of Biology, Southern University of Science and Technology, Shenzhen, China Institute for Integrative Biology of the Cell (I2BC), Université Paris-Sud, Orsay, France National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Japan Department of Pathology, University of Cambridge, United Kingdom Structural Biology, Genentech Inc., South San Francisco, CA, United States Division of Integrative Bioscience and Biotechnology, POSTECH, Pohang, South Korea Department of Biochemistry, The Bruce and Ruth Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel Institut für Zytobiologie, Philipps-Universität Marburg, Germany Department of Plant and Microbial Biology, University Zurich, Switzerland International Research Centre for Environmental Membrane Biology, Foshan University, Foshan, China Department of Life Science, Tokyo Institute of Technology, Yokohama, Japan Department of Molecular Biosciences, Northwestern University, Evanston, IL, United States Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Netherlands Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, United States Institute of Enzymology, Research Center for Natural Sciences (RCNS), Budapest, Hungary Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany Department of Biology/Microbial Physiology, Humboldt-University of Berlin, Germany Institute of Biology, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, China Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, United States Department of Biochemistry, Center for Biophysics and Quantitative Biology, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-ChampaignIL, United States Department of Biological Sciences and Centre for Molecular Simulation, University of CalgaryAB, Canada Institute for Integrated Cell-Material Sciences (WPI-iCeMS), KUIAS, Kyoto University, Japan Department of Molecular Biology, Princeton UniversityNJ, United States National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, United States Cited By :23 Export Date: 14 September 2021 CODEN: FEBLA Correspondence Address: Thomas, C.; Institute of Biochemistry, Germany; email: c.thomas@em.uni-frankfurt.de Correspondence Address: Tampé, R.; Institute of Biochemistry, Germany; email: tampe@em.uni-frankfurt.de AB - Members of the ATP-binding cassette (ABC) transporter superfamily translocate a broad spectrum of chemically diverse substrates. While their eponymous ATP-binding cassette in the nucleotide-binding domains (NBDs) is highly conserved, their transmembrane domains (TMDs) forming the translocation pathway exhibit distinct folds and topologies, suggesting that during evolution the ancient motor domains were combined with different transmembrane mechanical systems to orchestrate a variety of cellular processes. In recent years, it has become increasingly evident that the distinct TMD folds are best suited to categorize the multitude of ABC transporters. We therefore propose a new ABC transporter classification that is based on structural homology in the TMDs. © 2020 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies LA - English DB - MTMT ER - TY - JOUR AU - Csanády, László AU - Vergani, Paola AU - Gadsby, David C TI - STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL. JF - PHYSIOLOGICAL REVIEWS J2 - PHYSIOL REV VL - 99 PY - 2019 IS - 1 SP - 707 EP - 738 PG - 32 SN - 0031-9333 DO - 10.1152/physrev.00007.2018 UR - https://m2.mtmt.hu/api/publication/30387986 ID - 30387986 N1 - Department of Medical Biochemistry, Semmelweis UniversityBudapest, Hungary MTA-SE Ion Channel Research GroupBudapest, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY, United States Cited By :24 Export Date: 2 July 2020 CODEN: PHREA Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; cyclic AMP dependent protein kinase; cystic fibrosis transmembrane conductance regulator, 126880-72-6; Adenosine Triphosphate; Anions; Cystic Fibrosis Transmembrane Conductance Regulator Funding details: Cystic Fibrosis Trust, CF Funding text 1: Supported by Cystic Fibrosis Trust Project no. SRC 005 and Sparks Grant reference no. 15UCL04 (to P. Vergani), and Hungarian Academy of Sciences Lendület Grant LP2017–14/2017 and Cystic Fibrosis Foundation Research Grant CSANAD17G0 (to L. Csanády). Department of Medical Biochemistry, Semmelweis UniversityBudapest, Hungary MTA-SE Ion Channel Research GroupBudapest, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY, United States Cited By :60 Export Date: 11 August 2021 CODEN: PHREA Funding Agency and Grant Number: Cystic Fibrosis Trust [SRC 005]; Sparks Grant [15UCL04]; Hungarian Academy of Sciences Lendulet Grant [LP2017-14/2017]; Cystic Fibrosis Foundation Research Grant [CSANAD17G0] Funding text: Supported by Cystic Fibrosis Trust Project no. SRC 005 and Sparks Grant reference no. 15UCL04 (to P. Vergani), and Hungarian Academy of Sciences Lendulet Grant LP2017-14/2017 and Cystic Fibrosis Foundation Research Grant CSANAD17G0 (to L. Csanady). Department of Medical Biochemistry, Semmelweis UniversityBudapest, Hungary MTA-SE Ion Channel Research GroupBudapest, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY, United States Cited By :60 Export Date: 30 August 2021 CODEN: PHREA Department of Medical Biochemistry, Semmelweis UniversityBudapest, Hungary MTA-SE Ion Channel Research GroupBudapest, Hungary Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY, United States Cited By :60 Export Date: 31 August 2021 CODEN: PHREA AB - The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter superfamily but functions as an anion channel crucial for salt and water transport across epithelial cells. CFTR dysfunction, because of mutations, causes cystic fibrosis (CF). The anion-selective pore of the CFTR protein is formed by its two transmembrane domains (TMDs) and regulated by its cytosolic domains: two nucleotide binding domains (NBDs) and a regulatory (R) domain. Channel activation requires phosphorylation of the R domain by cAMP-dependent protein kinase (PKA), and pore opening and closing (gating) of phosphorylated channels is driven by ATP binding and hydrolysis at the NBDs. This review summarizes available information on structure and mechanism of the CFTR protein, with a particular focus on atomic-level insight gained from recent cryo-electron microscopic structures and on the molecular mechanisms of channel gating and its regulation. The pharmacological mechanisms of small molecules targeting CFTR's ion channel function, aimed at treating patients suffering from CF and other diseases, are briefly discussed. LA - English DB - MTMT ER - TY - JOUR AU - Liu, F AU - Zhang, Z AU - Csanády, László AU - Gadsby, DC AU - Chen, J TI - Molecular Structure of the Human CFTR Ion Channel JF - CELL J2 - CELL VL - 169 PY - 2017 IS - 1 SP - 85 EP - 95.e8 SN - 0092-8674 DO - 10.1016/j.cell.2017.02.024 UR - https://m2.mtmt.hu/api/publication/3210856 ID - 3210856 N1 - Cited By :244 Export Date: 9 March 2022 CODEN: CELLB Correspondence Address: Chen, J.; Laboratory of Membrane Biophysics and Biology, 1230 York Avenue, United States Chemicals/CAS: adenosine triphosphatase, 37289-25-1, 9000-83-3; adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; arginine, 1119-34-2, 15595-35-4, 7004-12-8, 74-79-3; cyclic AMP dependent protein kinase; cysteine, 4371-52-2, 52-89-1, 52-90-4; cystic fibrosis transmembrane conductance regulator, 126880-72-6; lysine, 56-87-1, 6899-06-5, 70-54-2; multidrug resistance associated protein 1; proline, 147-85-3, 7005-20-1; protein, 67254-75-5; serine, 56-45-1, 6898-95-9; Adenosine Triphosphate; CFTR protein, human; CFTR protein, zebrafish; Cystic Fibrosis Transmembrane Conductance Regulator; Zebrafish Proteins Funding details: LP2012-39/2012 Funding details: Howard Hughes Medical Institute, HHMI Funding details: Cystic Fibrosis Foundation, CFF, CSANAD15G0 Funding details: Rockefeller University Funding text 1: We thank Eric Gouaux for the expression vector, Mark Ebrahim and Johanna Sotiris at the Rockefeller Evelyn Gruss Lipper Cryo-Electron Microscopy Resource Center for assistance in data collection, and Sarah McCarry for editing this manuscript. This work is supported by the Rockefeller University (to J.C. and D.C.G), the Howard Hughes Medical Institute (to J.C.), and MTA-Momentum (LP2012-39/2012) and Cystic Fibrosis Foundation (CSANAD15G0) grants (to L.C.). AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 Å structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo-EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function. © 2017 Elsevier Inc. LA - English DB - MTMT ER - TY - JOUR AU - László, L AU - Sarkadi, Balázs AU - Hegedűs, Tamás TI - Jump into a new fold-A homology based model for the ABCG2/BCRP multidrug transporter JF - PLOS ONE J2 - PLOS ONE VL - 11 PY - 2016 IS - 10 SN - 1932-6203 DO - 10.1371/journal.pone.0164426 UR - https://m2.mtmt.hu/api/publication/3135666 ID - 3135666 AB - ABCG2/BCRP is a membrane protein, involved in xenobiotic and endobiotic transport in key pharmacological barriers and drug metabolizing organs, in the protection of stem cells, and in multidrug resistance of cancer. Pharmacogenetic studies implicated the role of ABCG2 in response to widely used medicines and anticancer agents, as well as in gout. Its Q141K variant exhibits decreased functional expression thus increased drug accumulation and decreased urate secretion. Still, there has been no reliable molecular model available for this protein, as the published structures of other ABC transporters could not be properly fitted to the ABCG2 topology and experimental data. The recently published high resolution structure of a close homologue, the ABCG5-ABCG8 heterodimer, revealed a new ABC transporter fold, unique for ABCG proteins. Here we present a structural model of the ABCG2 homodimer based on this fold and detail the experimental results supporting this model. In order to describe the effect of mutations on structure and dynamics, and characterize substrate recognition and cholesterol regulation we performed molecular dynamics simulations using full length ABCG2 protein embedded in a membrane bilayer and in silico docking simulations. Our results show that in the Q141K variant the introduced positive charge diminishes the interaction between the nucleotide binding and transmembrane domains and the R482G variation alters the orientation of transmembrane helices. Moreover, the R482 position, which plays a role the substrate specificity of the transporter, is located in one of the substrate binding pockets identified by the in silico docking calculations. In summary, the ABCG2 model and in silico simulations presented here may have significant impact on understanding drug distribution and toxicity, as well as drug development against cancer chemotherapy resistance or gout. © 2016 László 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. LA - English DB - MTMT ER - TY - JOUR AU - Veit, Gudio AU - Avramescu, Radu G AU - Chiang, Annette N AU - Houck, Scott A AU - Cai, Zhiwei AU - Peters, Kathryn W AU - Hong, Jeong S AU - Pollard, Harvey B AU - Guggino, William B AU - Balch, William E AU - Skach, William R AU - Cutting, Garry R AU - Frizzell, Raymond A AU - Sheppard, David N AU - Cyr, Douglas M AU - Sorscher, Eric J AU - Brodsky, Jeffrey L AU - Lukács, Gergely TI - From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations JF - MOLECULAR BIOLOGY OF THE CELL J2 - MOL BIOL CELL VL - 27 PY - 2016 IS - 3 SP - 424 EP - 433 PG - 10 SN - 1059-1524 DO - 10.1091/mbc.E14-04-0935 UR - https://m2.mtmt.hu/api/publication/25803207 ID - 25803207 N1 - Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Department of Physiology, United States Department of Biochemistry, United States GRASP, McGill University, Montréal, QC H3G 1Y6, Canada Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States Marsico Lung Institute, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States Department of Cellular, Developmental, and Integrative Biology, University of Alabama, Birmingham, AL 35294, United States Department of Anatomy, Physiology and Genetics and Center for Medical Proteomics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, United States KMcKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States Scripps Research Institute, Department of Chemical Physiology, Skaggs Institute of Chemical Physiology, San Diego, CA 92037, United States Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, United States Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States Cited By :224 Export Date: 10 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; GRASP, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, United States Department of Biochemistry, United States GRASP, McGill University, Montréal, QC H3G 1Y6, Canada Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States Marsico Lung Institute, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States Department of Cellular, Developmental, and Integrative Biology, University of Alabama, Birmingham, AL 35294, United States Department of Anatomy, Physiology and Genetics and Center for Medical Proteomics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, United States KMcKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States Scripps Research Institute, Department of Chemical Physiology, Skaggs Institute of Chemical Physiology, San Diego, CA 92037, United States Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, United States Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States Cited By :225 Export Date: 11 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; GRASP, Canada; email: gergely.lukacs@mcgill.ca Funding Agency and Grant Number: National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NO1-HL28187, IAA-A-HL-14-007.001, R01 DK, CFF CUTT13A1, CUTTXX0, R01-DK068196, P30-DK072506, CFFT FRIZZE05X0]; Cystic Fibrosis Foundation (CFF) [NIH DK51870, TRDRP23RT-0012, HL095524]; CFFT [SHEPPA14XX0, BROD-SK13XX0, NIH GM75061]; Cystic Fibrosis Trust; CFF Research Development Program, CFFT [SORSCH05XXO, SORSCH14XXO]; CF Canada [CFFT Lukacs13XXO, NIH DK075302]; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); CF Canada Studentship; Canada Research ChairNatural Resources CanadaCanadian Forest ServiceCanada Research Chairs; Cystic Fibrosis Trust [SRC005] Funding Source: researchfish; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL095524] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P30DK072482, R01DK068196, R01DK044003, R01DK075302, R01DK051870, P30DK079307, P30DK072506] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM056981, R01GM067785, R01GM075061] Funding Source: NIH RePORTER Funding text: We thank the members of the CFTR Folding Consortium, the CFTR Theratype Group, C. M. Penland, and K. Tuggle (Cystic Fibrosis Foundation, Bethesda, MD) for their valuable support. The work described here was supported by the following institutions and grants: National Institutes of Health (NIH) NO1-HL28187 and IAA-A-HL-14-007.001 to H.B.P.; Cystic Fibrosis Foundation (CFF), NIH DK51870, TRDRP23RT-0012, and HL095524 to W.E.B.; NIH R01 DK, CFF CUTT13A1, and CUTTXX0 to G.R.C.; CFFT SHEPPA14XX0 and Cystic Fibrosis Trust to D.N.S.; NIH R01-DK068196, P30-DK072506, and CFFT FRIZZE05X0 to R.A.F.; NIH RO1 GM56981 and CFFT CYR13XX0 to D.M.C.; the CFF Research Development Program, CFFT SORSCH05XXO, and SORSCH14XXO to E.J.S.; CFFT BROD-SK13XX0 and NIH GM75061 to J.L.B.; CF Canada, CFFT Lukacs13XXO, NIH DK075302, and Canadian Institutes of Health Research to G.L.L. R.G.A. was supported by CF Canada Studentship; G.L.L. is a recipient of a Canada Research Chair. Department of Physiology, United States Department of Biochemistry, United States GRASP, McGill University, Montréal, QC H3G 1Y6, Canada Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States Marsico Lung Institute, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States Department of Cellular, Developmental, and Integrative Biology, University of Alabama, Birmingham, AL 35294, United States Department of Anatomy, Physiology and Genetics and Center for Medical Proteomics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, United States KMcKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States Scripps Research Institute, Department of Chemical Physiology, Skaggs Institute of Chemical Physiology, San Diego, CA 92037, United States Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, United States Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States Cited By :226 Export Date: 28 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; GRASP, Canada; email: gergely.lukacs@mcgill.ca Funding Agency and Grant Number: National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NO1-HL28187, IAA-A-HL-14-007.001, R01 DK, CFF CUTT13A1, CUTTXX0, R01-DK068196, P30-DK072506, CFFT FRIZZE05X0]; Cystic Fibrosis Foundation (CFF) [NIH DK51870, TRDRP23RT-0012, HL095524]; CFFT [SHEPPA14XX0, BROD-SK13XX0, NIH GM75061]; Cystic Fibrosis Trust; CFF Research Development Program, CFFT [SORSCH05XXO, SORSCH14XXO]; CF Canada [CFFT Lukacs13XXO, NIH DK075302]; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); CF Canada Studentship; Canada Research ChairNatural Resources CanadaCanadian Forest ServiceCanada Research Chairs; Cystic Fibrosis Trust [SRC005] Funding Source: researchfish; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL095524] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P30DK079307, P30DK072506, R01DK044003, R01DK068196, R01DK051870, R01DK075302, P30DK072482] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM067785, R01GM075061, R01GM056981] Funding Source: NIH RePORTER Funding text: We thank the members of the CFTR Folding Consortium, the CFTR Theratype Group, C. M. Penland, and K. Tuggle (Cystic Fibrosis Foundation, Bethesda, MD) for their valuable support. The work described here was supported by the following institutions and grants: National Institutes of Health (NIH) NO1-HL28187 and IAA-A-HL-14-007.001 to H.B.P.; Cystic Fibrosis Foundation (CFF), NIH DK51870, TRDRP23RT-0012, and HL095524 to W.E.B.; NIH R01 DK, CFF CUTT13A1, and CUTTXX0 to G.R.C.; CFFT SHEPPA14XX0 and Cystic Fibrosis Trust to D.N.S.; NIH R01-DK068196, P30-DK072506, and CFFT FRIZZE05X0 to R.A.F.; NIH RO1 GM56981 and CFFT CYR13XX0 to D.M.C.; the CFF Research Development Program, CFFT SORSCH05XXO, and SORSCH14XXO to E.J.S.; CFFT BROD-SK13XX0 and NIH GM75061 to J.L.B.; CF Canada, CFFT Lukacs13XXO, NIH DK075302, and Canadian Institutes of Health Research to G.L.L. R.G.A. was supported by CF Canada Studentship; G.L.L. is a recipient of a Canada Research Chair. Department of Physiology, United States Department of Biochemistry, United States GRASP, McGill University, Montréal, QC H3G 1Y6, Canada Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States Marsico Lung Institute, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States Department of Cellular, Developmental, and Integrative Biology, University of Alabama, Birmingham, AL 35294, United States Department of Anatomy, Physiology and Genetics and Center for Medical Proteomics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, United States KMcKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States Scripps Research Institute, Department of Chemical Physiology, Skaggs Institute of Chemical Physiology, San Diego, CA 92037, United States Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, United States Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States Cited By :226 Export Date: 29 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; GRASP, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, United States Department of Biochemistry, United States GRASP, McGill University, Montréal, QC H3G 1Y6, Canada Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States Marsico Lung Institute, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States Department of Cellular, Developmental, and Integrative Biology, University of Alabama, Birmingham, AL 35294, United States Department of Anatomy, Physiology and Genetics and Center for Medical Proteomics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, United States KMcKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States Scripps Research Institute, Department of Chemical Physiology, Skaggs Institute of Chemical Physiology, San Diego, CA 92037, United States Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, United States Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States Cited By :226 Export Date: 30 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; GRASP, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, United States Department of Biochemistry, United States GRASP, McGill University, Montréal, QC H3G 1Y6, Canada Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States Marsico Lung Institute, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States Department of Cellular, Developmental, and Integrative Biology, University of Alabama, Birmingham, AL 35294, United States Department of Anatomy, Physiology and Genetics and Center for Medical Proteomics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, United States KMcKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States Scripps Research Institute, Department of Chemical Physiology, Skaggs Institute of Chemical Physiology, San Diego, CA 92037, United States Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, United States Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States Cited By :226 Export Date: 31 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; GRASP, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, United States Department of Biochemistry, United States GRASP, McGill University, Montréal, QC H3G 1Y6, Canada Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, United States Marsico Lung Institute, School of Medicine, University of North Carolina, Chapel Hill, NC 27514, United States School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States Department of Cellular, Developmental, and Integrative Biology, University of Alabama, Birmingham, AL 35294, United States Department of Anatomy, Physiology and Genetics and Center for Medical Proteomics, Uniformed Services University of Health Sciences, Bethesda, MD 20814, United States KMcKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States Scripps Research Institute, Department of Chemical Physiology, Skaggs Institute of Chemical Physiology, San Diego, CA 92037, United States Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, United States Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States Cited By :226 Export Date: 1 September 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; GRASP, Canada; email: gergely.lukacs@mcgill.ca LA - English DB - MTMT ER - TY - JOUR AU - Dobson, László AU - Reményi, István AU - Tusnády, Gábor TI - CCTOP: a Consensus Constrained TOPology prediction web server. JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 43 PY - 2015 IS - W1 SP - W408 EP - W412 SN - 0305-1048 DO - 10.1093/nar/gkv451 UR - https://m2.mtmt.hu/api/publication/2918485 ID - 2918485 LA - English DB - MTMT ER - TY - JOUR AU - Dobson, László AU - Reményi, István AU - Tusnády, Gábor TI - The human transmembrane proteome JF - BIOLOGY DIRECT J2 - BIOL DIRECT VL - 10 PY - 2015 PG - 18 SN - 1745-6150 DO - 10.1186/s13062-015-0061-x UR - https://m2.mtmt.hu/api/publication/2905250 ID - 2905250 N1 - Cited By :74 Export Date: 29 September 2023 Correspondence Address: Tusnády, G.E.; 'Momentum' Membrane Protein Bioinformatics Research Group, PO Box 7, Hungary; email: tusnady.gabor@ttk.mta.hu AB - Background: Transmembrane proteins have important roles in cells, as they are involved in energy production, signal transduction, cell-cell interaction, cell-cell communication and more. In human cells, they are frequently targets for pharmaceuticals; therefore, knowledge about their properties and structure is crucial. Topology of transmembrane proteins provide a low resolution structural information, which can be a starting point for either laboratory experiments or modelling their 3D structures. Results: Here, we present a database of the human α-helical transmembrane proteome, including the predicted and/or experimentally established topology of each transmembrane protein, together with the reliability of the prediction. In order to distinguish transmembrane proteins in the proteome as well as for topology prediction, we used a newly developed consensus method (CCTOP) that incorporates recent state of the art methods, with tested accuracies on a novel human benchmark protein set. CCTOP utilizes all available structure and topology data as well as bioinformatical evidences for topology prediction in a probabilistic framework provided by the hidden Markov model. This method shows the highest accuracy (98.5 % for discrinimating between transmembrane and non-transmembrane proteins and 84 % for per protein topology prediction) among the dozen tested topology prediction methods. Analysis of the human proteome with the CCTOP indicates that it contains 4998 (26 %) transmembrane proteins. Besides predicting topology, reliability of the predictions is estimated as well, and it is demonstrated that the per protein prediction accuracies of more than 60 % of the predictions are over 98 % on the benchmark sets and most probably on the predicted human transmembrane proteome too. Conclusions: Here, we present the most accurate prediction of the human transmembrane proteome together with the experimental topology data. These data, as well as various statistics about the human transmembrane proteins and their topologies can be downloaded from and can be visualized at the website of the human transmembrane proteome (http://htp.enzim.hu). Reviewers: This article was reviewed by Dr. Sandor Pongor, Dr. Michael Galperin and Dr. Pascale Gaudet (nominated by Dr Michael Galperin). © 2015 Dobson et al.; licensee BioMed Central. LA - English DB - MTMT ER - TY - JOUR AU - Kozma, Dániel AU - Simon, István AU - Tusnády, Gábor TI - PDBTM: Protein Data Bank of transmembrane proteins after 8 years JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 41 PY - 2013 IS - D1 SP - D524 EP - D529 SN - 0305-1048 DO - 10.1093/nar/gks1169 UR - https://m2.mtmt.hu/api/publication/2149788 ID - 2149788 N1 - Lendület Membrane Protein Bioinformatics Research Group, Institute of Enzymology, MTA RCNS, PO Box 7, H-1518 Budapest, Hungary Protein Structure Research Group, Institute of Enzymology, MTA RCNS, PO Box 7, H-1518 Budapest, Hungary Cited By :199 Export Date: 29 September 2023 CODEN: NARHA Correspondence Address: Tusnády, G.E.; Lendület Membrane Protein Bioinformatics Research Group, PO Box 7, H-1518 Budapest, Hungary; email: tusnady.gabor@ttk.mta.hu LA - English DB - MTMT ER - TY - JOUR AU - Serohijos, AW AU - Hegedűs, Tamás AU - Riordan, JR AU - Dokholyan, NV TI - Diminished self-chaperoning activity of the DeltaF508 mutant of CFTR results in protein misfolding. JF - PLOS COMPUTATIONAL BIOLOGY J2 - PLOS COMPUT BIOL VL - 4 PY - 2008 IS - 2 SP - e1000008 SN - 1553-734X DO - 10.1371/journal.pcbi.1000008 UR - https://m2.mtmt.hu/api/publication/1506345 ID - 1506345 N1 - Serohijos AW and Hegedus T authors contributed equally to this work. Funding Agency and Grant Number: Cystic Fibrosis FoundationItalian Cystic Fibrosis Research Foundation [DOKHOL07I0]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK051870]; AHA Predoctoral FellowshipAmerican Heart Association [0715215U]; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK051870] Funding Source: NIH RePORTER Funding text: This work is partially supported by Cystic Fibrosis Foundation grant DOKHOL07I0 (to NVD) and by the NIH grant DK051870 (to JRR). AWRS is supported by an AHA Predoctoral Fellowship, 0715215U. Department of Physics and Astronomy, University of North Carolina Chapel Hill, Chapel Hill, NC, United States Department of Biochemistry and Biophysics, University of North Carolina Chapel Hill, Chapel Hill, NC, United States Cystic Fibrosis Research Center, University of North Carolina Chapel Hill, Chapel Hill, NC, United States Cited By :33 Export Date: 31 August 2021 Correspondence Address: Serohijos, A. W. R.; Department of Physics and Astronomy, , Chapel Hill, NC, United States Department of Physics and Astronomy, University of North Carolina Chapel Hill, Chapel Hill, NC, United States Department of Biochemistry and Biophysics, University of North Carolina Chapel Hill, Chapel Hill, NC, United States Cystic Fibrosis Research Center, University of North Carolina Chapel Hill, Chapel Hill, NC, United States Cited By :33 Export Date: 2 September 2021 Correspondence Address: Serohijos, A. W. R.; Department of Physics and Astronomy, , Chapel Hill, NC, United States AB - The absence of a functional ATP Binding Cassette (ABC) protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) from apical membranes of epithelial cells is responsible for cystic fibrosis (CF). Over 90% of CF patients carry at least one mutant allele with deletion of phenylalanine at position 508 located in the N-terminal nucleotide binding domain (NBD1). Biochemical and cell biological studies show that the DeltaF508 mutant exhibits inefficient biosynthetic maturation and susceptibility to degradation probably due to misfolding of NBD1 and the resultant misassembly of other domains. However, little is known about the direct effect of the Phe508 deletion on the NBD1 folding, which is essential for rational design strategies of cystic fibrosis treatment. Here we show that the deletion of Phe508 alters the folding dynamics and kinetics of NBD1, thus possibly affecting the assembly of the complete CFTR. Using molecular dynamics simulations, we find that meta-stable intermediate states appearing on wild type and mutant folding pathways are populated differently and that their kinetic accessibilities are distinct. The structural basis of the increased misfolding propensity of the DeltaF508 NBD1 mutant is the perturbation of interactions in residue pairs Q493/P574 and F575/F578 found in loop S7-H6. As a proof-of-principle that the S7-H6 loop conformation can modulate the folding kinetics of NBD1, we virtually design rescue mutations in the identified critical interactions to force the S7-H6 loop into the wild type conformation. Two redesigned NBD1-DeltaF508 variants exhibited significantly higher folding probabilities than the original NBD1-DeltaF508, thereby partially rescuing folding ability of the NBD1-DeltaF508 mutant. We propose that these observed defects in folding kinetics of mutant NBD1 may also be modulated by structures separate from the 508 site. The identified structural determinants of increased misfolding propensity of NBD1-DeltaF508 are essential information in correcting this pathogenic mutant. LA - English DB - MTMT ER - TY - JOUR AU - Bakos, Éva AU - Evers, R AU - Calenda, G AU - Tusnády, Gábor AU - Szakács, Gergely AU - Váradi, András AU - Sarkadi, Balázs TI - Characterization of the amino-terminal regions in the human multidrug resistance protein (MRP1) JF - JOURNAL OF CELL SCIENCE J2 - J CELL SCI VL - 113 PY - 2000 IS - 24 SP - 4451 EP - 4461 PG - 11 SN - 0021-9533 UR - https://m2.mtmt.hu/api/publication/151391 ID - 151391 N1 - Cited By :100 Export Date: 10 February 2023 CODEN: JNCSA Correspondence Address: Sarkadi, B.; Natl. Inst. of Haematology/Immunol., , H-1113 Budapest, Hungary; email: B.Sarkadi@ohvi.hu Chemicals/CAS: ATP-Binding Cassette Transporters; Multidrug Resistance-Associated Proteins; P-Glycoprotein; Recombinant Fusion Proteins AB - The human multidrug resistance protein (MRP1) contributes to drug resistance in cancer cells. In addition to an MDR1-like core, MRP1 contains an N-terminal membrane-bound (TMD0) region and a cytoplasmic linker (L0), both characteristic of several members of the MRP family. In order to study the role of the TMD0 and L0 regions, we constructed various truncated and mutated MRP1, and chimeric MRP1-MDR1 molecules, which were expressed in insect (Sf9) and polarized mammalian (MDCKII) cells. The function of the various proteins was examined in isolated membrane vesicles by measuring the transport of leukotriene C4 and other glutathione conjugates, and by vanadate-dependent nucleotide occlusion. Cellular localization, and glutathione-conjugate and drug transport, were also studied in MDCKII cells. We found that chimeric proteins consisting of N-terminal fragments of MRP1 fused to the N terminus of MDR1 preserved the transport, nucleotide occlusion and apical membrane routing of wild-type MDR1. As shown before, MRP1 without TMD0L0 (ΔMRP1), was non-functional and localized intracellularly, so we investigated the coexpression of ΔMRP1 with the isolated L0 region. Coexpression yielded a functional MRP1 molecule in Sf9 cells and routing to the lateral membrane in MDCKII cells. Interestingly, the L0 peptide was found to be associated with membranes in Sf9 cells and could only be solubilized by urea or detergent. A 10-amino-acid deletion in a predicted amphipathic region of L0 abolished its attachment to the membrane and eliminated MRP1 transport function, but did not affect membrane routing. Taken together, these experiments suggest that the L0 region forms a distinct domain within MRP1, which interacts with hydrophobic membrane regions and with the core region of MRP1. LA - English DB - MTMT ER -