TY - JOUR AU - Rabeh, WM AU - Bossard, F AU - Xu, HJ AU - Okiyoneda, T AU - Bagdany, M AU - Mulvihill, CM AU - Du, K AU - di, Bernardo S AU - Liu, YH AU - Konermann, L AU - Roldan, A AU - Lukács, Gergely TI - Correction of Both NBD1 Energetics and Domain Interface Is Required to Restore Delta F508 CFTR Folding and Function JF - CELL J2 - CELL VL - 148 PY - 2012 IS - 1-2 SP - 150 EP - 163 PG - 14 SN - 0092-8674 DO - 10.1016/j.cell.2011.11.024 UR - https://m2.mtmt.hu/api/publication/22804152 ID - 22804152 N1 - Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Funding Agency and Grant Number: Cystic Fibrosis Foundation Therapeutics Inc; Cystic Fibrosis Canada; NIH-NIDDKUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [DK075302]; Canadian Institute of Health ResearchCanadian Institutes of Health Research (CIHR); Canadian Foundation for InnovationCanada Foundation for Innovation; GRASP; Canadian Cystic Fibrosis Foundation; 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) [R01DK075302] Funding Source: NIH RePORTER Funding text: We thank H. Lewis, C. Lima, J.R. Riordan, J. Young, E. Buck, and the Cystic Fibrosis Foundation Therapeutics, Inc. for valuable reagents and feedbacks, J. Young and D. Thomas for providing access to the Chirascan and qPCR instruments, and N. Kartner, G. Veit, J. Szapor, D. Scicchitano, and F. Pianofor for helpful comments on the manuscript. We thank the Cystic Fibrosis Foundation Therapeutics Inc, Cystic Fibrosis Canada, NIH-NIDDK (grant number DK075302), Canadian Institute of Health Research, and the Canadian Foundation for Innovation for operating and infrastructure support. W.M.R. was partially supported by GRASP and a Canadian Cystic Fibrosis Foundation postdoctoral fellowship. L.K. and G.L.L. are holders of Canada Research Chairs. Department of Physiology, McGill University, Montréal, QC H3E 1Y6, Canada GRASP, McGill University, Montréal, QC H3E 1Y6, Canada Department of Chemistry, University of Western Ontario, London, ON N6A 5B7, Canada Department of Sciences, New York University, P.O. Box 129188, Abu Dhabi, United Arab Emirates Cited By :199 Export Date: 27 August 2021 CODEN: CELLB Correspondence Address: Lukacs, G.L.; Department of Physiology, , Montréal, QC H3E 1Y6, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, McGill University, Montréal, QC H3E 1Y6, Canada GRASP, McGill University, Montréal, QC H3E 1Y6, Canada Department of Chemistry, University of Western Ontario, London, ON N6A 5B7, Canada Department of Sciences, New York University, P.O. Box 129188, Abu Dhabi, United Arab Emirates Cited By :199 Export Date: 30 August 2021 CODEN: CELLB Correspondence Address: Lukacs, G.L.; Department of Physiology, , Montréal, QC H3E 1Y6, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, McGill University, Montréal, QC H3E 1Y6, Canada GRASP, McGill University, Montréal, QC H3E 1Y6, Canada Department of Chemistry, University of Western Ontario, London, ON N6A 5B7, Canada Department of Sciences, New York University, P.O. Box 129188, Abu Dhabi, United Arab Emirates Cited By :199 Export Date: 31 August 2021 CODEN: CELLB Correspondence Address: Lukacs, G.L.; Department of Physiology, , Montréal, QC H3E 1Y6, Canada; email: gergely.lukacs@mcgill.ca LA - English DB - MTMT ER - TY - JOUR AU - Veit, Guido AU - Bossard, Florian AU - Goepp, Julie AU - Verkman, A S AU - Galietta, Luis J V AU - Hanrahan, John W AU - Lukács, Gergely TI - Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia. JF - MOLECULAR BIOLOGY OF THE CELL J2 - MOL BIOL CELL VL - 23 PY - 2012 IS - 21 SP - 4188 EP - 4202 PG - 15 SN - 1059-1524 DO - 10.1091/mbc.E12-06-0424 UR - https://m2.mtmt.hu/api/publication/32127991 ID - 32127991 N1 - Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Funding Agency and Grant Number: EMBOEuropean Molecular Biology Organization (EMBO); Fonds de Recherche du Quebec-Sante Postdoctoral Training Award; Richard & Edith Strauss Fellowship; National Institutes of Health-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); Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); Cystic Fibrosis Foundation TherapeuticsItalian Cystic Fibrosis Research Foundation; Canadian Foundation for InnovationCanada Foundation for Innovation; Cystic Fibrosis Canada Breathe Program; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [HL73856]; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL073856] 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) [R01DK075302] Funding Source: NIH RePORTER Funding text: We acknowledge H. Salah's contribution to the initial phase of the study, D. Gruenert for the parental CFBE14o- cell line, and W. Gallin for the anti-E-cadherin antibody. G.V. was supported by an EMBO fellowship and in part by a Fonds de Recherche du Quebec-Sante Postdoctoral Training Award. F.B. was a recipient of a Richard & Edith Strauss Fellowship. Work performed in the authors' laboratories was supported by the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases, the Canadian Institutes of Health Research, the Cystic Fibrosis Foundation Therapeutics, the Canadian Foundation for Innovation, the Cystic Fibrosis Canada Breathe Program, and National Institutes of Health Grant HL73856. G.L. is holder of a Canada Research Chair. Department of Physiology, McGill University, Montréal, QC H3G 1Y6, Canada Department of Medicine and Physiology, University of California, San Francisco, San Francisco, CA 94143-0521, United States Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, I-16147 Genoa, Italy Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montréal, QC H3G 1Y6, Canada Cited By :77 Export Date: 30 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; Department of Physiology, , Montréal, QC H3G 1Y6, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, McGill University, Montréal, QC H3G 1Y6, Canada Department of Medicine and Physiology, University of California, San Francisco, San Francisco, CA 94143-0521, United States Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, I-16147 Genoa, Italy Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montréal, QC H3G 1Y6, Canada Cited By :77 Export Date: 31 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G.L.; Department of Physiology, , Montréal, QC H3G 1Y6, Canada; email: gergely.lukacs@mcgill.ca AB - Cystic fibrosis (CF) is caused by the functional expression defect of the CF transmembrane conductance regulator (CFTR) chloride channel at the apical plasma membrane. Impaired bacterial clearance and hyperactive innate immune response are hallmarks of the CF lung disease, yet the existence of and mechanism accounting for the innate immune defect that occurs before infection remain controversial. Inducible expression of either CFTR or the calcium-activated chloride channel TMEM16A attenuated the proinflammatory cytokines interleukin-6 (IL-6), IL-8, and CXCL1/2 in two human respiratory epithelial models under air-liquid but not liquid-liquid interface culture. Expression of wild-type but not the inactive G551D-CFTR indicates that secretion of the chemoattractant IL-8 is inversely proportional to CFTR channel activity in cftr(∆F508/∆F508) immortalized and primary human bronchial epithelia. Similarly, direct but not P2Y receptor-mediated activation of TMEM16A attenuates IL-8 secretion in respiratory epithelia. Thus augmented proinflammatory cytokine secretion caused by defective anion transport at the apical membrane may contribute to the excessive and persistent lung inflammation in CF and perhaps in other respiratory diseases associated with documented down-regulation of CFTR (e.g., chronic obstructive pulmonary disease). Direct pharmacological activation of TMEM16A offers a potential therapeutic strategy to reduce the inflammation of CF airway epithelia. LA - English DB - MTMT ER - TY - JOUR AU - Phuan, Puay-Wah AU - Yang, Baoxue AU - Knapp, John M AU - Wood, Alex B AU - Lukács, Gergely AU - Kurth, Mark J AU - Verkman, A S TI - Cyanoquinolines with independent corrector and potentiator activities restore ΔPhe508-cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis. JF - MOLECULAR PHARMACOLOGY J2 - MOL PHARMACOL VL - 80 PY - 2011 IS - 4 SP - 683 EP - 693 PG - 11 SN - 0026-895X DO - 10.1124/mol.111.073056 UR - https://m2.mtmt.hu/api/publication/32127993 ID - 32127993 N1 - Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Funding Agency and Grant Number: National Institutes of Health 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) [DK72517, DK075302, DK86125, DK35124]; National Institutes of Health National Heart, Lung, and Blood InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [HL73856]; National Institute of Health National Institute of Biomedical Imaging and BioengineeringUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Biomedical Imaging & Bioengineering (NIBIB) [EB00415]; National Institute of Health National Eye InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [EY135740]; Cystic Fibrosis FoundationItalian Cystic Fibrosis Research Foundation; Canadian Cystic Fibrosis Foundation; Canada Research ChairNatural Resources CanadaCanadian Forest ServiceCanada Research Chairs; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL073856] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERINGUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Biomedical Imaging & Bioengineering (NIBIB) [R37EB000415, R01EB000415] 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) [RC1DK086125, P30DK072517, R01DK075302, R01DK035124, R37DK035124] Funding Source: NIH RePORTER Funding text: This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK72517, DK075302, DK86125, DK35124]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL73856]; the National Institute of Health National Institute of Biomedical Imaging and Bioengineering [Grant EB00415]; the National Institute of Health National Eye Institute [Grant EY135740]; the Cystic Fibrosis Foundation; the Canadian Cystic Fibrosis Foundation; and a Canada Research Chair (to G.L.L.). Departments of Medicine and Physiology, University of California, San Francisco, CA, United States Department of Chemistry, University of California, Davis, CA, United States Department of Physiology, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC, Canada Cited By :51 Export Date: 27 August 2021 CODEN: MOPMA Correspondence Address: Verkman, A.S.; 1246 Health Sciences East Tower, , San Francisco, CA 94143-0521, United States; email: alan.verkman@ucsf.edu Departments of Medicine and Physiology, University of California, San Francisco, CA, United States Department of Chemistry, University of California, Davis, CA, United States Department of Physiology, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC, Canada Cited By :51 Export Date: 28 August 2021 CODEN: MOPMA Correspondence Address: Verkman, A.S.; 1246 Health Sciences East Tower, , San Francisco, CA 94143-0521, United States; email: alan.verkman@ucsf.edu Departments of Medicine and Physiology, University of California, San Francisco, CA, United States Department of Chemistry, University of California, Davis, CA, United States Department of Physiology, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC, Canada Cited By :51 Export Date: 30 August 2021 CODEN: MOPMA Correspondence Address: Verkman, A.S.; 1246 Health Sciences East Tower, , San Francisco, CA 94143-0521, United States; email: alan.verkman@ucsf.edu Departments of Medicine and Physiology, University of California, San Francisco, CA, United States Department of Chemistry, University of California, Davis, CA, United States Department of Physiology, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC, Canada Cited By :51 Export Date: 1 September 2021 CODEN: MOPMA Correspondence Address: Verkman, A.S.; 1246 Health Sciences East Tower, , San Francisco, CA 94143-0521, United States; email: alan.verkman@ucsf.edu AB - The ΔPhe508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein impairs its folding, stability, and chloride channel gating. Although small molecules that separately correct defective ΔPhe508-CFTR folding/cellular processing ("correctors") or chloride channel gating ("potentiators") have been discovered and are in clinical trials, single compounds with bona fide dual corrector and potentiator activities have not been identified. Here, screening of ∼110,000 small molecules not tested previously revealed a cyanoquinoline class of compounds with independent corrector and potentiator activities (termed CoPo). Analysis of 180 CoPo analogs revealed 6 compounds with dual corrector and potentiator activities and 13 compounds with only potentiator activity. N-(2-((3-Cyano-5,7-dimethylquinolin-2-yl)amino)ethyl)-3-methoxybenzamide (CoPo-22), which was synthesized in six steps in 52% overall yield, had low micromolar EC(50) for ΔPhe508-CFTR corrector and potentiator activities by short-circuit current assay. Maximal corrector and potentiator activities were comparable with those conferred by the bithiazole Corr-4a and the flavone genistein, respectively. CoPo-22 also activated wild-type and G551D CFTR chloride conductance within minutes in a forskolin-dependent manner. Compounds with dual corrector and potentiator activities may be useful for single-drug treatment of cystic fibrosis caused by ΔPhe508 mutation. LA - English DB - MTMT ER - TY - JOUR AU - Okiyoneda, Tsukasa AU - Barrière, Hervé AU - Bagdány, Miklós AU - Rabeh, Wael M AU - Du, Kai AU - Höhfeld, Jörg AU - Young, Jason C AU - Lukács, Gergely TI - Peripheral protein quality control removes unfolded CFTR from the plasma membrane. JF - SCIENCE J2 - SCIENCE VL - 329 PY - 2010 IS - 5993 SP - 805 EP - 810 PG - 6 SN - 0036-8075 DO - 10.1126/science.1191542 UR - https://m2.mtmt.hu/api/publication/32127998 ID - 32127998 N1 - Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Funding Agency and Grant Number: Canadian Cystic Fibrosis Foundation; Groupe de Recherche Axe sur la Structure des Proteines (GRASP); Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG); Canadian Institute of Health Resources; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA; Cystic Fibrosis Foundation TherapeuticsItalian Cystic Fibrosis Research Foundation; Canadian Foundation for InnovationCanada Foundation for Innovation Funding text: We thank J. Tavares and C. M. Mulvihill for CHIP purification and generating CFTR-His10 cells, respectively; H. Stenmark for Hrs antibody; and H. Lewis, C. Lima, and K. Iwai for NBD1-3S, SUMO, Ulp1, and UbcH5 plasmids, respectively. Lamp1, Lamp2, and CD63 antibodies were developed by J. August and J. Hildreth (University of Iowa). T.O. and W.M.R. were supported by a Canadian Cystic Fibrosis Foundation and a Groupe de Recherche Axe sur la Structure des Proteines (GRASP) postdoctoral fellowship, respectively. This work was supported by grants to J. H. from Deutsche Forschungsgemeinschaft, J.C.Y. and G.L.L. from the Canadian Institute of Health Resources, NIH, Cystic Fibrosis Foundation Therapeutics, the Canadian Cystic Fibrosis Foundation, and the Canadian Foundation for Innovation. J.C.Y. and G.L.L. are holders of Canada Research Chairs. Department of Physiology, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC H3G 1Y6, Canada Cell Biology Institute, University Bonn, D-53121 Bonn, Germany Department of Biochemistry, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC H3G 1Y6, Canada Cited By :302 Export Date: 27 August 2021 CODEN: SCIEA Correspondence Address: Lukacs, G. L.; Department of Physiology, , Montreal, QC H3G 1Y6, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC H3G 1Y6, Canada Cell Biology Institute, University Bonn, D-53121 Bonn, Germany Department of Biochemistry, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC H3G 1Y6, Canada Cited By :302 Export Date: 31 August 2021 CODEN: SCIEA Correspondence Address: Lukacs, G. L.; Department of Physiology, , Montreal, QC H3G 1Y6, Canada; email: gergely.lukacs@mcgill.ca Department of Physiology, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC H3G 1Y6, Canada Cell Biology Institute, University Bonn, D-53121 Bonn, Germany Department of Biochemistry, Groupe de Recherche Axé Sur la Structure des Protéine (GRASP), McGill University, Montreal, QC H3G 1Y6, Canada Cited By :302 Export Date: 2 September 2021 CODEN: SCIEA Correspondence Address: Lukacs, G. L.; Department of Physiology, , Montreal, QC H3G 1Y6, Canada; email: gergely.lukacs@mcgill.ca AB - Therapeutic efforts to restore biosynthetic processing of the cystic fibrosis transmembrane conductance regulator lacking the F508 residue (DeltaF508CFTR) are hampered by ubiquitin-dependent lysosomal degradation of nonnative, rescued DeltaF508CFTR from the plasma membrane. Here, functional small interfering RNA screens revealed the contribution of chaperones, cochaperones, and ubiquitin-conjugating and -ligating enzymes to the elimination of unfolded CFTR from the cell surface, as part of a peripheral protein quality-control system. Ubiquitination of nonnative CFTR was required for efficient internalization and lysosomal degradation. This peripheral protein quality-control mechanism probably participates in the preservation of cellular homeostasis by degrading damaged plasma membrane proteins that have escaped from the endoplasmic reticulum quality control or are generated by environmental stresses in situ. LA - English DB - MTMT ER - TY - JOUR AU - Thibodeau, PH AU - Richardson, JM AU - Wang, W AU - Millen, L AU - Watson, J AU - Mendoza, JL AU - Du, K AU - Fischman, S AU - Senderowitz, H AU - Lukács, Gergely AU - Kirk, K AU - Thomas, PJ TI - The Cystic Fibrosis-causing Mutation Delta F508 Affects Multiple Steps in Cystic Fibrosis Transmembrane Conductance Regulator Biogenesis JF - JOURNAL OF BIOLOGICAL CHEMISTRY J2 - J BIOL CHEM VL - 285 PY - 2010 IS - 46 SP - 35825 EP - 35835 PG - 11 SN - 0021-9258 DO - 10.1074/jbc.M110.131623 UR - https://m2.mtmt.hu/api/publication/21364030 ID - 21364030 N1 - Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Funding Agency and Grant Number: National Institutes of Health NIDDKUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [49835, 75302]; Cystic Fibrosis FoundationItalian Cystic Fibrosis Research Foundation; Canadian Cystic Fibrosis Foundation; Canadian Foundation of InnovationCanada Foundation for Innovation; Canada Research ChairNatural Resources CanadaCanadian Forest ServiceCanada Research Chairs; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL058341] 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) [R37DK049835] Funding Source: NIH RePORTER Funding text: This work was supported, in whole or in part, by National Institutes of Health NIDDK Grants 49835 (to P.J.T.) and 75302 (to G.L.L.). This work was also supported by the Cystic Fibrosis Foundation (to P.J.T.) and the Canadian Cystic Fibrosis Foundation (to G.L.L.). The authors declare they have competing financial interests. The beta-galactosidase assay has been licensed to Reata Pharmaceuticals by The University of Texas Southwestern Medical Center at Dallas. P.J.T. is a founding scientist of Reata Pharmaceuticals.; Supported by the Canadian Foundation of Innovation and recipient of a Canada Research Chair. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294, United States Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada Epix Pharmaceuticals, Lexington, MA 02421-3112, United States Dept. of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States Dept. of Chemistry, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan 52900, Israel Cited By :124 Export Date: 28 August 2021 CODEN: JBCHA Correspondence Address: Thomas, P. J.; Department of Physiology, , Dallas, TX 75390, United States; email: Philip.Thomas@UTSouthwestern.edu Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294, United States Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada Epix Pharmaceuticals, Lexington, MA 02421-3112, United States Dept. of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States Dept. of Chemistry, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan 52900, Israel Cited By :124 Export Date: 31 August 2021 CODEN: JBCHA Correspondence Address: Thomas, P. J.; Department of Physiology, , Dallas, TX 75390, United States; email: Philip.Thomas@UTSouthwestern.edu Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States Molecular Biophysics Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294, United States Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada Epix Pharmaceuticals, Lexington, MA 02421-3112, United States Dept. of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States Dept. of Chemistry, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan 52900, Israel Cited By :124 Export Date: 2 September 2021 CODEN: JBCHA Correspondence Address: Thomas, P. J.; Department of Physiology, , Dallas, TX 75390, United States; email: Philip.Thomas@UTSouthwestern.edu LA - English DB - MTMT ER - TY - JOUR AU - Du, K AU - Lukács, Gergely TI - Cooperative Assembly and Misfolding of CFTR Domains In Vivo JF - MOLECULAR BIOLOGY OF THE CELL J2 - MOL BIOL CELL VL - 20 PY - 2009 IS - 7 SP - 1903 EP - 1915 PG - 13 SN - 1059-1524 DO - 10.1091/mbc.E08-09-0950 UR - https://m2.mtmt.hu/api/publication/21961629 ID - 21961629 N1 - Megjegyzés-25241002 Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Funding Agency and Grant Number: Cystic Fibrosis Foundation TherapeuticsItalian Cystic Fibrosis Research Foundation; CCFF; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR); National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); Canadian Foundation for InnovationCanada Foundation for Innovation; Canada Research ChairNatural Resources CanadaCanadian Forest ServiceCanada Research Chairs Funding text: We thank J. Young and members of the Lukacs laboratory for careful reading of the manuscript and helpful suggestions, M. Bagdany for generating the RXR mutations, J. Riordan and A. Badwell for providing anti-CFTR antibodies, and A. Davidson and C. A. Kaiser for the lambda cDNA. Work was supported by grants from the Cystic Fibrosis Foundation Therapeutics, the CCFF, the Canadian Institutes of Health Research, the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases), and the Canadian Foundation for Innovation. G.L.L. is a holder of a Canada Research Chair. Cited By :103 Export Date: 28 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G. L.; Department of Physiology, , Montreal, QC H3G 1Y6, Canada; email: gergely.lukacs@mcgill.ca Cited By :103 Export Date: 31 August 2021 CODEN: MBCEE Correspondence Address: Lukacs, G. L.; Department of Physiology, , Montreal, QC H3G 1Y6, Canada; email: gergely.lukacs@mcgill.ca LA - English DB - MTMT ER - TY - JOUR AU - He, L AU - Aleksandrov, AA AU - Serohijos, AW AU - Hegedűs, Tamás AU - Aleksandrov, LA AU - Cui, L AU - Dokholyan, NV AU - Riordan, JR TI - Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (CFTR) mediate regulation of channel gating. JF - JOURNAL OF BIOLOGICAL CHEMISTRY J2 - J BIOL CHEM VL - 283 PY - 2008 IS - 39 SP - 26383 EP - 26390 PG - 8 SN - 0021-9258 DO - 10.1074/jbc.M803894200 UR - https://m2.mtmt.hu/api/publication/1506344 ID - 1506344 N1 - GR: DK051619/DK/NIDDK NIH HHS/United States GR: R01 DK051619-08/DK/NIDDK NIH HHS/United States PMC: PMC2546535 OID: NLM: PMC2546535 Megjegyzés-25241010 Hiányzó Jelleg: 'JOUR\n\nArticle' Admin megjegyzés-25241010 tblcategory: (Category) ('JOUR\n\nArticle') #Jelleg Funding Agency and Grant Number: National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK051619]; Cystic Fibrosis FoundationItalian Cystic Fibrosis Research Foundation [DOKHOL07I0]; 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) [R01DK051619, R01DK051870] Funding Source: NIH RePORTER Funding text: This work was supported, in whole or in part, by National Institutes of Health Grant DK051619 (to J. R. R.). This work was also supported by Cystic Fibrosis Foundation Grant DOKHOL07I0 ( to N. V. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, United States Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599, United States Department of Physics and Astronomy, University of North Carolina, Chapel Hill, NC 27599, United States Molecular and Cellular Physics Program, University of North Carolina, Chapel Hill, NC 27599, United States Cystic Fibrosis Center, University of North Carolina, Chapel Hill, NC 27599, United States Cited By :95 Export Date: 31 August 2021 CODEN: JBCHA Correspondence Address: Riordan, J. R.; Department of Biochemistry and Biophysics, , Chapel Hill, NC 27599, United States; email: jack_riordan@med.unc.edu AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique ATP-binding cassette (ABC) ion channel mutated in patients with cystic fibrosis. The most common mutation, deletion of phenylalanine 508 (DeltaF508) and many other disease-associated mutations occur in the nucleotide binding domains (NBD) and the cytoplasmic loops (CL) of the membrane-spanning domains (MSD). A recently constructed computational model of the CFTR three-dimensional structure, supported by experimental data (Serohijos, A. W., Hegedus, T., Aleksandrov, A. A., He, L., Cui, L., Dokholyan, N. V., and Riordan, J. R. (2008) Proc. Natl. Acad. Sci. U. S. A. 105, 3256-3261) revealed that several of these mutations including DeltaF508 disrupted interfaces between these domains. Here we have used cysteine cross-linking experiments to verify all NBD/CL interfaces predicted by the structural model and observed that their cross-linking has a variety of different effects on channel gating. The interdomain contacts comprise aromatic clusters important for stabilization of the interfaces and also involve the Q-loops and X-loops that are in close proximity to the ATP binding sites. Cross-linking of all domain-swapping contacts between NBDs and MSD cytoplasmic loops in opposite halves of the protein rapidly and reversibly arrest single channel gating while those in the same halves have lesser impact. These results reinforce the idea that mediation of regulatory signals between cytoplasmic- and membrane-integrated domains of the CFTR channel apparently relies on an array of precise but highly dynamic interdomain structural joints. LA - English DB - MTMT ER - TY - JOUR AU - Serohijos, AW AU - Hegedűs, Tamás AU - Aleksandrov, AA AU - He, L AU - Cui, L AU - Dokholyan, NV AU - Riordan, JR TI - Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 105 PY - 2008 IS - 9 SP - 3256 EP - 3261 PG - 6 SN - 0027-8424 DO - 10.1073/pnas.0800254105 UR - https://m2.mtmt.hu/api/publication/1506347 ID - 1506347 N1 - GR: DK051619/DK/NIDDK NIH HHS/United States PMC: PMC2265173 OID: NLM: PMC2265173 Megjegyzés-25241008 Hiányzó Jelleg: 'JOUR\n\nArticle' Admin megjegyzés-25241008 tblcategory: (Category) ('JOUR\n\nArticle') #Jelleg Funding Agency and Grant Number: NIDDK NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [DK051619, R01 DK051619] Funding Source: Medline; 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) [R01DK051619] Funding Source: NIH RePORTER Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, United States Department of Physics and Astronomy, University of North Carolina, Chapel Hill, NC 27599, United States Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599, United States Molecular and Cellular Biophysics Program, University of North Carolina, Chapel Hill, NC 27599, United States Cystic Fibrosis Center, University of North Carolina, Chapel Hill, NC 27599, United States Cited By :293 Export Date: 31 August 2021 CODEN: PNASA Correspondence Address: Dokholyan, N. V.; Department of Biochemistry and Biophysics, , Chapel Hill, NC 27599, United States; email: dokh@med.unc.edu Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, United States Department of Physics and Astronomy, University of North Carolina, Chapel Hill, NC 27599, United States Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599, United States Molecular and Cellular Biophysics Program, University of North Carolina, Chapel Hill, NC 27599, United States Cystic Fibrosis Center, University of North Carolina, Chapel Hill, NC 27599, United States Cited By :293 Export Date: 2 September 2021 CODEN: PNASA Correspondence Address: Dokholyan, N. V.; Department of Biochemistry and Biophysics, , Chapel Hill, NC 27599, United States; email: dokh@med.unc.edu AB - Deletion of phenylalanine-508 (Phe-508) from the N-terminal nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ATP-binding cassette (ABC) transporter family, disrupts both its folding and function and causes most cystic fibrosis. Most mutant nascent chains do not pass quality control in the ER, and those that do remain thermally unstable, only partially functional, and are rapidly endocytosed and degraded. Although the lack of the Phe-508 peptide backbone diminishes the NBD1 folding yield, the absence of the aromatic side chain is primarily responsible for defective CFTR assembly and channel gating. However, the site of interdomain contact by the side chain is unknown as is the high-resolution 3D structure of the complete protein. Here we present a 3D structure of CFTR, constructed by molecular modeling and supported biochemically, in which Phe-508 mediates a tertiary interaction between the surface of NBD1 and a cytoplasmic loop (CL4) in the C-terminal membrane-spanning domain (MSD2). This crucial cytoplasmic membrane interface, which is dynamically involved in regulation of channel gating, explains the known sensitivity of CFTR assembly to many disease-associated mutations in CL4 as well as NBD1 and provides a sharply focused target for small molecules to treat CF. In addition to identifying a key intramolecular site to be repaired therapeutically, our findings advance understanding of CFTR structure and function and provide a platform for focused biochemical studies of other features of this unique ABC ion channel. LA - English DB - MTMT ER - TY - JOUR AU - Cui, L AU - Aleksandrov, L AU - Chang, XB AU - Hou, YX AU - He, L AU - Hegedűs, Tamás AU - Gentzsch, M AU - Aleksandrov, A AU - Balch, WE AU - Riordan, JR TI - Domain interdependence in the biosynthetic assembly of CFTR. JF - JOURNAL OF MOLECULAR BIOLOGY J2 - J MOL BIOL VL - 365 PY - 2007 IS - 4 SP - 981 EP - 994 PG - 14 SN - 0022-2836 DO - 10.1016/j.jmb.2006.10.086 UR - https://m2.mtmt.hu/api/publication/1506348 ID - 1506348 N1 - Dept of Biochemistry and Biophysics, Cystic Fibrosis Center, University of North Carolina at Chapel Hill, NC 27599, United States Mayo Clinic College of Medicine, Scottsdale, AZ 85259, United States The Scripps Research Institute, Departments of Cell and Molecular Biology, The Institute for Childhood and Neglected Disease, La Jolla, CA 92307, United States Cited By :158 Export Date: 31 August 2021 CODEN: JMOBA Correspondence Address: Riordan, J.R.; Dept of Biochemistry and Biophysics, , NC 27599, United States; email: john_riordan@med.unc.edu AB - The dimerization of their two nucleotide binding domains (NBDs) in a so-called "nucleotide-sandwich" is the hallmark of ATP cassette binding (ABC) proteins and the basis of their catalytic activities. The major disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7), deletion of Phe508 in NBD1, does not grossly alter the structure of that domain but prevents conformational maturation of the whole CFTR protein, possibly by disrupting the native interaction between NBD1 and NBD2. However, the role of inter-domain interactions in CFTR folding has been brought into question by a recent report that all CFTR domains fold independently. Here we show that in addition to domain folding, correct inter-domain assembly is essential to form a stable unit that satisfies endoplasmic reticulum (ER) quality control. N-terminal domains depend on their more C-terminal neighbors, most essentially the second membrane-spanning domain (MSD2) but significantly, not NBD2. Wild-type C-terminal truncation constructs, completely devoid of NBD2 are transported out of the ER and to the cell surface where they form characteristic CFTR chloride channels with low open probability. The DeltaNBD2 wild-type protein matures and has similar stability as its full-length counterpart. Therefore, the catalytically crucial inter-NBD associations are not required to satisfy ER quality control mechanisms. The DeltaF508 mutation arrests the maturation of DeltaNBD2 just as it does full-length CFTR, indicating that DeltaF508 perturbs other portions of the molecule in addition to NBD2. We find that the mutation prevents formation of a compact MSD1, reflected in its susceptibility to protease digestion. This perturbation of MSD1 may in turn prevent its normal integration with MSD2. The dispensability of NBD2 in the folding of more N-terminal domains stands in contrast to the known hypersensitivity to proteolysis of NBD2 in the DeltaF508 protein. LA - English DB - MTMT ER - TY - JOUR AU - Hegedűs, Tamás AU - Aleksandrov, A AU - Cui, L AU - Gentzsch, M AU - Chang, XB AU - Riordan, JR TI - F508del CFTR with two altered RXR motifs escapes from ER quality control but its channel activity is thermally sensitive. JF - BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES J2 - BBA-BIOMEMBRANES VL - 1758 PY - 2006 IS - 5 SP - 565 EP - 572 PG - 8 SN - 0005-2736 DO - 10.1016/j.bbamem.2006.03.006 UR - https://m2.mtmt.hu/api/publication/1506349 ID - 1506349 N1 - GR: DK051870/DK/NIDDK NIH HHS/United States CIN: Biochim Biophys Acta. 2006 May;1758(5):563-4. PMID: 16712779 Funding Agency and Grant Number: 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; NIDDK NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [DK051870] Funding Source: Medline Department of Biochemistry and Biophysics and Cystic Fibrosis T, R Center, UNC, 5011 Thurston-Bowles Bldg, Chapel Hill, NC 27510-7248, United States Mayo Clinic College of Medicine, Mayo Clinic, Scottsdale, AZ 85259, United States Cited By :47 Export Date: 27 August 2021 CODEN: BBBMB Correspondence Address: Riordan, J.R.; Department of Biochemistry and Biophysics and Cystic Fibrosis T, 5011 Thurston-Bowles Bldg, Chapel Hill, NC 27510-7248, United States; email: john_riordan@med.unc.edu Department of Biochemistry and Biophysics and Cystic Fibrosis T, R Center, UNC, 5011 Thurston-Bowles Bldg, Chapel Hill, NC 27510-7248, United States Mayo Clinic College of Medicine, Mayo Clinic, Scottsdale, AZ 85259, United States Cited By :47 Export Date: 28 August 2021 CODEN: BBBMB Correspondence Address: Riordan, J.R.; Department of Biochemistry and Biophysics and Cystic Fibrosis T, 5011 Thurston-Bowles Bldg, Chapel Hill, NC 27510-7248, United States; email: john_riordan@med.unc.edu Department of Biochemistry and Biophysics and Cystic Fibrosis T, R Center, UNC, 5011 Thurston-Bowles Bldg, Chapel Hill, NC 27510-7248, United States Mayo Clinic College of Medicine, Mayo Clinic, Scottsdale, AZ 85259, United States Cited By :47 Export Date: 2 September 2021 CODEN: BBBMB Correspondence Address: Riordan, J.R.; Department of Biochemistry and Biophysics and Cystic Fibrosis T, 5011 Thurston-Bowles Bldg, Chapel Hill, NC 27510-7248, United States; email: john_riordan@med.unc.edu AB - Most cystic fibrosis (CF) patients carry the F508del mutation in the CFTR chloride channel protein resulting in its misassembly, retention in the endoplasmic reticulum (ER), and proteasomal degradation. Therefore, characterization of the retention and attempts to rescue the mutant CFTR are a major focus of CF research. Earlier, we had shown that four arginine-framed tripeptide (AFT) signals in CFTR participate in the quality control. Now we have mutated these four AFTs in all possible combinations and found that simultaneous inactivation of two of them (R29K and R555K) is necessary and sufficient to overcome F508del CFTR retention. Immunofluorescence staining of BHK cells expressing this variant indicates that it matures and is routed to the plasma membrane. Acquisition of at least some wild-type structure was detected in the pattern of proteolytic digestion fragments. Functional activity at the cell surface was evident in chloride efflux assays. However, single channel activity of the rescued mutant measured in planar lipid bilayers diminished as temperature was increased from 30 to 37 degrees C. These findings support the idea that absence of Phe 508 causes not only a kinetic folding defect but also steady-state structural instability. Therefore effective molecular therapies developed to alleviate disease caused by F508del and probably other misprocessing mutants will require overcoming both their kinetic and steady-state impacts. LA - English DB - MTMT ER - TY - JOUR AU - Du, K AU - Sharma, M AU - Lukács, Gergely TI - The F508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR JF - NATURE STRUCTURAL & MOLECULAR BIOLOGY J2 - NAT STRUCT MOL BIOL VL - 12 PY - 2005 IS - 1 SP - 17 EP - 25 PG - 9 SN - 1545-9993 DO - 10.1038/nsmb882 UR - https://m2.mtmt.hu/api/publication/24259179 ID - 24259179 N1 - Összes idézések száma a WoS-ban: 0 Journal Article; Research Support, Non-U.S. Gov't Hosp. for Sick Children Res. Inst., Program in Cell and Lung Biology, University of Toronto, Toronto, Ont. M5G 1X8, Canada Dept. of Lab. Med. and Pathobiology, University of Toronto, Ont. M5G 1X8, Canada Cited By :256 Export Date: 28 August 2021 CODEN: NSMBC Correspondence Address: Lukacs, G.L.; Hosp. for Sick Children Res. Inst., , Toronto, Ont. M5G 1X8, Canada; email: glukacs@sickkids.ca Hosp. for Sick Children Res. Inst., Program in Cell and Lung Biology, University of Toronto, Toronto, Ont. M5G 1X8, Canada Dept. of Lab. Med. and Pathobiology, University of Toronto, Ont. M5G 1X8, Canada Cited By :256 Export Date: 31 August 2021 CODEN: NSMBC Correspondence Address: Lukacs, G.L.; Hosp. for Sick Children Res. Inst., , Toronto, Ont. M5G 1X8, Canada; email: glukacs@sickkids.ca Hosp. for Sick Children Res. Inst., Program in Cell and Lung Biology, University of Toronto, Toronto, Ont. M5G 1X8, Canada Dept. of Lab. Med. and Pathobiology, University of Toronto, Ont. M5G 1X8, Canada Cited By :256 Export Date: 2 September 2021 CODEN: NSMBC Correspondence Address: Lukacs, G.L.; Hosp. for Sick Children Res. Inst., , Toronto, Ont. M5G 1X8, Canada; email: glukacs@sickkids.ca LA - English DB - MTMT ER - TY - JOUR AU - Pedemonte, N AU - Lukács, Gergely AU - Du, K AU - Caci, E AU - Zegarra, Moran O AU - Galietta, L J V AU - Verkman, A S TI - Small-molecule correctors of defective Delta F508-CFTR cellular processing identified by high-throughput screening JF - JOURNAL OF CLINICAL INVESTIGATION J2 - J CLIN INVEST VL - 115 PY - 2005 IS - 9 SP - 2564 EP - 2571 PG - 8 SN - 0021-9738 DO - 10.1172/JCI24898 UR - https://m2.mtmt.hu/api/publication/20200717 ID - 20200717 N1 - Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Funding Agency and Grant Number: NEI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [EY13574, R01 EY013574] Funding Source: Medline; NHLBI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [HL59198, R01 HL059198, R01 HL073856, HL73856] Funding Source: Medline; NIBIB NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Biomedical Imaging & Bioengineering (NIBIB) [R01 EB000415, R37 EB000415, EB00415] Funding Source: Medline; NIDDK NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [DK72517, P30 DK072517, R01 DK035124, R37 DK035124, DK35124] Funding Source: Medline; TelethonFondazione Telethon [GP0296Y01] Funding Source: Medline; NATIONAL EYE INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [R01EY013574] Funding Source: NIH RePORTER; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL059198, R01HL073856] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERINGUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Biomedical Imaging & Bioengineering (NIBIB) [R37EB000415, R01EB000415] 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) [R01DK035124, P30DK072517, R37DK035124] Funding Source: NIH RePORTER Department of Medicine, UCSF, San Francisco, CA, United States Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy Program in Cell and Lung Biology, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ont., Canada 1246 Health Sciences East Tower, University of California, San Francisco, San Francisco, CA 94143-0521, United States Cited By :448 Export Date: 28 August 2021 CODEN: JCINA Correspondence Address: Verkman, A.S.; 1246 Health Sciences East Tower, , San Francisco, CA 94143-0521, United States; email: verkman@itsa.ucsf.edu Department of Medicine, UCSF, San Francisco, CA, United States Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy Program in Cell and Lung Biology, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ont., Canada 1246 Health Sciences East Tower, University of California, San Francisco, San Francisco, CA 94143-0521, United States Cited By :448 Export Date: 31 August 2021 CODEN: JCINA Correspondence Address: Verkman, A.S.; 1246 Health Sciences East Tower, , San Francisco, CA 94143-0521, United States; email: verkman@itsa.ucsf.edu Department of Medicine, UCSF, San Francisco, CA, United States Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy Program in Cell and Lung Biology, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ont., Canada 1246 Health Sciences East Tower, University of California, San Francisco, San Francisco, CA 94143-0521, United States Cited By :448 Export Date: 1 September 2021 CODEN: JCINA Correspondence Address: Verkman, A.S.; 1246 Health Sciences East Tower, , San Francisco, CA 94143-0521, United States; email: verkman@itsa.ucsf.edu Department of Medicine, UCSF, San Francisco, CA, United States Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy Program in Cell and Lung Biology, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ont., Canada 1246 Health Sciences East Tower, University of California, San Francisco, San Francisco, CA 94143-0521, United States Cited By :448 Export Date: 2 September 2021 CODEN: JCINA Correspondence Address: Verkman, A.S.; 1246 Health Sciences East Tower, , San Francisco, CA 94143-0521, United States; email: verkman@itsa.ucsf.edu LA - English DB - MTMT ER - TY - JOUR AU - Egan, Marie E AU - Pearson, Marilyn AU - Weiner, Scott A AU - Rajendran, Vanathy AU - Rubin, Daniel AU - Glöckner-Pagel, Judith AU - Canny, Susan AU - Du, Kai AU - Lukács, Gergely AU - Caplan, Michael J TI - Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. JF - SCIENCE J2 - SCIENCE VL - 304 PY - 2004 IS - 5670 SP - 600 EP - 602 PG - 3 SN - 0036-8075 DO - 10.1126/science.1093941 UR - https://m2.mtmt.hu/api/publication/32128020 ID - 32128020 N1 - Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Funding Agency and Grant Number: 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) [R01DK053428, P01DK017433] 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) [R01GM042136] Funding Source: NIH RePORTER; NIDDK NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01 DK053428, DK17433, DK53428] Funding Source: Medline; NIGMS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [GM42136] Funding Source: Medline Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8026, United States Dept. of Cell. and Molec. Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8026, United States Hospital for Sick Children, Dept. of Lab. Med. and Pathobiology, University of Toronto, 555 University Avenue, Toronto, Ont. M5G 1X8, Canada Cited By :501 Export Date: 2 September 2021 CODEN: SCIEA Correspondence Address: Caplan, M.J.; Dept. of Cell. and Molec. Physiology, 333 Cedar Street, New Haven, CT 06520-8026, United States; email: michael.caplan@yale.edu AB - Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, DeltaF508, results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin is a nontoxic Ca-adenosine triphosphatase pump inhibitor that can be administered to humans safely. Oral administration of curcumin to homozygous DeltaF508 CFTR mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of DeltaF508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, curcumin treatment may be able to correct defects associated with the homozygous expression of DeltaF508 CFTR. LA - English DB - MTMT ER - TY - JOUR AU - Fiser, András AU - Sali, A TI - ModLoop: automated modeling of loops in protein structures JF - BIOINFORMATICS J2 - BIOINFORMATICS VL - 19 PY - 2003 IS - 18 SP - 2500 EP - 2501 PG - 2 SN - 1367-4803 DO - 10.1093/bioinformatics/btg362 UR - https://m2.mtmt.hu/api/publication/1128838 ID - 1128838 AB - ModLoop is a web server for automated modeling of loops in protein structures. The input is the atomic coordinates of the protein structure in the Protein Data Bank format, and the specification of the starting and ending residues of one or more segments to be modeled, containing no more than 20 residues in total. The output is the coordinates of the non-hydrogen atoms in the modeled segments. A user provides the input to the server via a simple web interface, and receives the output by e-mail. The server relies on the loop modeling routine in MODELLER that predicts the loop conformations by satisfaction of spatial restraints, without relying on a database of known protein structures. For a rapid response, ModLoop runs on a cluster of Linux PC computers. LA - English DB - MTMT ER - TY - JOUR AU - Zhang, F AU - Kartner, N AU - Lukács, Gergely TI - Limited proteolysis as a probe for arrested conformational maturation of delta F508 CFTR. JF - NATURE STRUCTURAL BIOLOGY J2 - NAT STRUCT BIOL VL - 5 PY - 1998 IS - 3 SP - 180 EP - 183 PG - 4 SN - 1072-8368 DO - 10.1038/nsb0398-180 UR - https://m2.mtmt.hu/api/publication/32128041 ID - 32128041 N1 - Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. AB - Deletion of phenylalanine 508 (delta F508) in the cystic fibrosis transmembrane-conductance regulator (CFTR) prevents the otherwise functional protein from reaching the plasma membrane and is the leading cause of cystic fibrosis. Indirect evidence suggests that the mutant protein, delta F508 CFTR, is misfolded. We address this issue directly, using comparative limited proteolysis of CFTR at steady steady state and during biosynthesis in the native microsomal environment. Distinct protease susceptibilities suggest that cytosolic domain conformations of wild type and delta F508 CFTR differ, not only near F508, but globally. Moreover, delta F508 CFTR proteolytic cleavage patterns were indistinguishable from those of the early folding intermediate of wild type CFTR. The results suggest that the delta F508 mutation causes the accumulation of a form of the protein that resembles an intermediate in the biogenesis of the wild type CFTR, rather than induces the production of non-native variant. LA - English DB - MTMT ER -