@article{MTMT:34798555,
	title = {Functional Consequences of CFTR Interactions in Cystic Fibrosis},
	url = {https://m2.mtmt.hu/api/publication/34798555},
	author = {Ramananda, Y. and Naren, A.P. and Arora, K.},
	doi = {10.3390/ijms25063384},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {25},
	unique-id = {34798555},
	issn = {1661-6596},
	abstract = {Cystic fibrosis (CF) is a fatal autosomal recessive disorder caused by the loss of function mutations within a single gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR is a chloride channel that regulates ion and fluid transport across various epithelia. The discovery of CFTR as the CF gene and its cloning in 1989, coupled with extensive research that went into the understanding of the underlying biological mechanisms of CF, have led to the development of revolutionary therapies in CF that we see today. The highly effective modulator therapies have increased the survival rates of CF patients and shifted the epidemiological landscape and disease prognosis. However, the differential effect of modulators among CF patients and the presence of non-responders and ineligible patients underscore the need to develop specialized and customized therapies for a significant number of patients. Recent advances in the understanding of the CFTR structure, its expression, and defined cellular compositions will aid in developing more precise therapies. As the lifespan of CF patients continues to increase, it is becoming critical to clinically address the extra-pulmonary manifestations of CF disease to improve the quality of life of the patients. In-depth analysis of the molecular signature of different CF organs at the transcriptional and post-transcriptional levels is rapidly advancing and will help address the etiological causes and variability of CF among patients and develop precision medicine in CF. In this review, we will provide an overview of CF disease, leading to the discovery and characterization of CFTR and the development of CFTR modulators. The later sections of the review will delve into the key findings derived from single-molecule and single-cell-level analyses of CFTR, followed by an exploration of disease-relevant protein complexes of CFTR that may ultimately define the etiological course of CF disease. © 2024 by the authors.},
	keywords = {Humans; MUTATION; MUTATION; metabolism; signal transduction; signal transduction; human; Quality of Life; Quality of Life; personalized medicine; cystic fibrosis; cystic fibrosis; cystic fibrosis; CFTR protein, human; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis Transmembrane Conductance Regulator; Precision Medicine; CFTR modulators; CFTR interactors; single-cell analyses of CFTR},
	year = {2024},
	eissn = {1422-0067}
}

@article{MTMT:34191189,
	title = {CFTR function, pathology and pharmacology at single-molecule resolution},
	url = {https://m2.mtmt.hu/api/publication/34191189},
	author = {Levring, J. and Terry, D.S. and Kilic, Z. and Fitzgerald, G. and Blanchard, S. and Chen, J.},
	doi = {10.1038/s41586-023-05854-7},
	journal-iso = {NATURE},
	journal = {NATURE},
	volume = {616},
	unique-id = {34191189},
	issn = {0028-0836},
	abstract = {The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes1. Alterations in CFTR cause cystic fibrosis, a fatal disease without a cure2,3. Electrophysiological properties of CFTR have been analysed for decades4–6. The structure of CFTR, determined in two globally distinct conformations, underscores its evolutionary relationship with other ATP-binding cassette transporters. However, direct correlations between the essential functions of CFTR and extant structures are lacking at present. Here we combine ensemble functional measurements, single-molecule fluorescence resonance energy transfer, electrophysiology and kinetic simulations to show that the two nucleotide-binding domains (NBDs) of human CFTR dimerize before channel opening. CFTR exhibits an allosteric gating mechanism in which conformational changes within the NBD-dimerized channel, governed by ATP hydrolysis, regulate chloride conductance. The potentiators ivacaftor and GLPG1837 enhance channel activity by increasing pore opening while NBDs are dimerized. Disease-causing substitutions proximal (G551D) or distal (L927P) to the ATPase site both reduce the efficiency of NBD dimerization. These findings collectively enable the framing of a gating mechanism that informs on the search for more efficacious clinical therapies. © 2023, The Author(s).},
	keywords = {Humans; metabolism; PHARMACOLOGY; ARTICLE; KINETICS; HYDROLYSIS; HYDROLYSIS; human; Electrophysiology; ATP-Binding Cassette Transporters; controlled study; molecular analysis; pathology; pathology; Dimerization; Dimerization; Homeostasis; PROTEIN FUNCTION; Adenosine Triphosphate; Adenosine Triphosphate; Fluorescence Resonance Energy Transfer; ABC transporter; conformational transition; cystic fibrosis; cystic fibrosis; adenosine triphosphatase; CFTR protein, human; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic Fibrosis Transmembrane Conductance Regulator; chloride conductance; allosterism; disease prevalence; ivacaftor; Single Molecule Imaging; nucleotide binding protein},
	year = {2023},
	eissn = {1476-4687},
	pages = {606-614}
}

@article{MTMT:33636409,
	title = {Optimization of CFTR gating through the evolution of its extracellular loops},
	url = {https://m2.mtmt.hu/api/publication/33636409},
	author = {Simon, Márton and Csanády, László},
	doi = {10.1085/jgp.202213264},
	journal-iso = {J GEN PHYSIOL},
	journal = {JOURNAL OF GENERAL PHYSIOLOGY},
	volume = {155},
	unique-id = {33636409},
	issn = {0022-1295},
	year = {2023},
	eissn = {1540-7748},
	orcid-numbers = {Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:34232792,
	title = {Estimating the true stability of the prehydrolytic outward-facing state in an ABC protein.},
	url = {https://m2.mtmt.hu/api/publication/34232792},
	author = {Simon, Márton and Iordanov, Iordan and Szöllősi, András and Csanády, László},
	doi = {10.7554/eLife.90736},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {12},
	unique-id = {34232792},
	issn = {2050-084X},
	abstract = {CFTR, the anion channel mutated in cystic fibrosis patients, is a model ABC protein whose ATP-driven conformational cycle is observable at single-molecule level in patch-clamp recordings. Bursts of CFTR pore openings are coupled to tight dimerization of its two nucleotide-binding domains (NBDs) and in wild-type (WT) channels are mostly terminated by ATP hydrolysis. The slow rate of non-hydrolytic closure - which determines how tightly bursts and ATP hydrolysis are coupled - is unknown, as burst durations of catalytic site mutants span a range of ~200-fold. Here, we show that Walker A mutation K1250A, Walker B mutation D1370N, and catalytic glutamate mutations E1371S and E1371Q all completely disrupt ATP hydrolysis. True non-hydrolytic closing rate of WT CFTR approximates that of K1250A and E1371S. That rate is slowed ~15-fold in E1371Q by a non-native inter-NBD H-bond, and accelerated ~15-fold in D1370N. These findings uncover unique features of the NBD interface in human CFTR.},
	keywords = {ZEBRAFISH; Xenopus; molecular biophysics; Structural biology; D-loop; composite ATP-binding site; flickery closure; mutant cycle},
	year = {2023},
	eissn = {2050-084X},
	orcid-numbers = {Iordanov, Iordan/0000-0001-8251-5857; Szöllősi, András/0000-0002-5570-4609; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:33629018,
	title = {Molecular dynamics study of Cl− permeation through cystic fibrosis transmembrane conductance regulator (CFTR)},
	url = {https://m2.mtmt.hu/api/publication/33629018},
	author = {Zeng, Z.W. and Linsdell, P. and Pomès, R.},
	doi = {10.1007/s00018-022-04621-7},
	journal-iso = {CELL MOL LIFE SCI},
	journal = {CELLULAR AND MOLECULAR LIFE SCIENCES},
	volume = {80},
	unique-id = {33629018},
	issn = {1420-682X},
	abstract = {The recent elucidation of atomistic structures of Cl− channel CFTR provides opportunities for understanding the molecular basis of cystic fibrosis. Despite having been activated through phosphorylation and provided with ATP ligands, several near-atomistic cryo-EM structures of CFTR are in a closed state, as inferred from the lack of a continuous passage through a hydrophobic bottleneck region located in the extracellular portion of the pore. Here, we present repeated, microsecond-long molecular dynamics simulations of human CFTR solvated in a lipid bilayer and aqueous NaCl. At equilibrium, Cl− ions enter the channel through a lateral intracellular portal and bind to two distinct cationic sites inside the channel pore but do not traverse the narrow, de-wetted bottleneck. Simulations conducted in the presence of a strong hyperpolarizing electric field led to spontaneous Cl− translocation events through the bottleneck region of the channel, suggesting that the protein relaxed to a functionally open state. Conformational changes of small magnitude involving transmembrane helices 1 and 6 preceded ion permeation through diverging exit routes at the extracellular end of the pore. The pore bottleneck undergoes wetting prior to Cl− translocation, suggesting that it acts as a hydrophobic gate. Although permeating Cl− ions remain mostly hydrated, partial dehydration occurs at the binding sites and in the bottleneck. The observed Cl− pathway is largely consistent with the loci of mutations that alter channel conductance, anion binding, and ion selectivity, supporting the model of the open state of CFTR obtained in the present study. © 2023, The Author(s).},
	keywords = {MOLECULAR MECHANISM; membrane protein; PROTEIN DYNAMICS; ATP-binding cassette; Ion solvation; Pore hydration},
	year = {2023},
	eissn = {1420-9071}
}

@article{MTMT:32111898,
	title = {Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation},
	url = {https://m2.mtmt.hu/api/publication/32111898},
	author = {Della, Sala A. and Prono, G. and Hirsch, E. and Ghigo, A.},
	doi = {10.3389/fphys.2021.690247},
	journal-iso = {FRONT PHYSIOL},
	journal = {FRONTIERS IN PHYSIOLOGY},
	volume = {12},
	unique-id = {32111898},
	year = {2021},
	eissn = {1664-042X}
}

@article{MTMT:32573094,
	title = {Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond},
	url = {https://m2.mtmt.hu/api/publication/32573094},
	author = {Simon, Márton and Csanády, László},
	doi = {10.7554/eLife.74693},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {10},
	unique-id = {32573094},
	issn = {2050-084X},
	abstract = {The phosphorylation-activated anion channel cystic fibrosis transmembrane conductance regulator (CFTR) is gated by an ATP hydrolysis cycle at its two cytosolic nucleotide-binding domains, and is essential for epithelial salt-water transport. A large number of CFTR mutations cause cystic fibrosis. Since recent breakthrough in targeted pharmacotherapy, CFTR mutants with impaired gating are candidates for stimulation by potentiator drugs. Thus, understanding the molecular pathology of individual mutations has become important. The relatively common R117H mutation affects an extracellular loop, but nevertheless causes a strong gating defect. Here, we identify a hydrogen bond between the side chain of arginine 117 and the backbone carbonyl group of glutamate 1124 in the cryo-electronmicroscopic structure of phosphorylated, ATP-bound CFTR. We address the functional relevance of that interaction for CFTR gating using macroscopic and microscopic inside-out patch-clamp recordings. Employing thermodynamic double-mutant cycles, we systematically track gating-state-dependent changes in the strength of the R117-E1124 interaction. We find that the H-bond is formed only in the open state, but neither in the short-lived 'flickery' nor in the long-lived 'interburst' closed state. Loss of this H-bond explains the strong gating phenotype of the R117H mutant, including robustly shortened burst durations and strongly reduced intraburst open probability. The findings may help targeted potentiator design.},
	keywords = {PHOSPHORYLATION; AMINO-ACIDS; CONFORMATIONAL-CHANGES; IDENTIFICATION; TRANSMEMBRANE CONDUCTANCE REGULATOR; KINETIC-ANALYSIS; CFTR; gating defect; ABC protein; ATP-BINDING; CL-CHANNELS; class III mutant; R117H},
	year = {2021},
	eissn = {2050-084X},
	orcid-numbers = {Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:32274498,
	title = {Functional stability of CFTR depends on tight binding of ATP at its degenerate ATP-binding site},
	url = {https://m2.mtmt.hu/api/publication/32274498},
	author = {Yeh, Han- I and Yu, Ying-Chun and Kuo, Pei-Lun and Tsai, Chun-Kuang and Huang, Hsin-Tuan and Hwang, Tzyh-Chang},
	doi = {10.1113/JP281933},
	journal-iso = {J PHYSIOL-LONDON},
	journal = {JOURNAL OF PHYSIOLOGY-LONDON},
	volume = {599},
	unique-id = {32274498},
	issn = {0022-3751},
	abstract = {Opening of the cystic fibrosis transmembrane conductance regulator (CFTR) channel is coupled to the motion of its two nucleotide-binding domains: they form a heterodimer sandwiching two functionally distinct ATP-binding sites (sites 1 and 2). While active ATP hydrolysis in site 2 triggers rapid channel closure, the functional role of stable ATP binding in the catalysis-incompetent (or degenerate) site 1, a feature conserved in many other ATP-binding cassette (ABC) transporter proteins, remains elusive. Here, we found that CFTR loses its prompt responsiveness to ATP after the channel is devoid of ATP for tens to hundreds of seconds. Mutants with weakened ATP binding in site 1 and the most prevalent disease-causing mutation, F508del, are more vulnerable to ATP depletion. In contrast, strengthening ligand binding in site 1 with N-6-(2-phenylethyl)-ATP, a high-affinity ATP analogue, or abolishing ATP hydrolysis in site 2 by the mutation D1370N, helps sustain a durable function of the otherwise unstable mutant channels. Thus, tight binding of ATP in the degenerate ATP-binding site is crucial to the functional stability of CFTR. Small molecules targeting site 1 may bear therapeutic potential to overcome the membrane instability of F508del-CFTR.},
	keywords = {ABC transporter; ATP HYDROLYSIS; cystic fibrosis; anion channel; gating},
	year = {2021},
	eissn = {1469-7793},
	pages = {4625-4642},
	orcid-numbers = {Hwang, Tzyh-Chang/0000-0002-1967-8167}
}

@article{MTMT:31732979,
	title = {The role of the degenerate nucleotide binding site in type I ABC exporters},
	url = {https://m2.mtmt.hu/api/publication/31732979},
	author = {Stockner, T. and Gradisch, R. and Schmitt, L.},
	doi = {10.1002/1873-3468.13997},
	journal-iso = {FEBS LETT},
	journal = {FEBS LETTERS},
	volume = {594},
	unique-id = {31732979},
	issn = {0014-5793},
	abstract = {ATP-binding cassette (ABC) transporters are fascinating molecular machines that are capable of transporting a large variety of chemically diverse compounds. The energy required for translocation is derived from binding and hydrolysis of ATP. All ABC transporters share a basic architecture and are composed of two transmembrane domains and two nucleotide binding domains (NBDs). The latter harbor all conserved sequence motifs that hallmark the ABC transporter superfamily. The NBDs form the nucleotide binding sites (NBSs) in their interface. Transporters with two active NBSs are called canonical transporters, while ABC exporters from eukaryotic organisms, including humans, frequently have a degenerate NBS1 containing noncanonical residues that strongly impair ATP hydrolysis. Here, we summarize current knowledge on degenerate ABC transporters. By integrating structural information with biophysical and biochemical evidence of asymmetric function, we develop a model for the transport cycle of degenerate ABC transporters. We will elaborate on the unclear functional advantages of a degenerate NBS. © 2020 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies},
	keywords = {ABC TRANSPORTERS; degenerate nucleotide binding site; transport cycle model; type I exporter},
	year = {2020},
	eissn = {1873-3468},
	pages = {3815-3838}
}

@article{MTMT:30881158,
	title = {Cholesterol Interaction Directly Enhances Intrinsic Activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)},
	url = {https://m2.mtmt.hu/api/publication/30881158},
	author = {Chin, Stephanie and Ramjeesingh, Mohabir and Hung, Maurita and Ereno-Oreba, June and Cui, Hong and Laselva, Onofrio and Julien, Jean-Philippe and Bear, Christine E.},
	doi = {10.3390/cells8080804},
	journal-iso = {CELLS-BASEL},
	journal = {CELLS},
	volume = {8},
	unique-id = {30881158},
	abstract = {The recent cryo-electron microscopy structures of zebrafish and the human cystic fibrosis transmembrane conductance regulator (CFTR) provided unprecedented insights into putative mechanisms underlying gating of its anion channel activity. Interestingly, despite predictions based on channel activity measurements in biological membranes, the structure of the detergent purified, phosphorylated, and ATP-bound human CFTR protein did not reveal a stably open conduction pathway. This study tested the hypothesis that the functional properties of the detergent solubilized CFTR protein used for structural determinations are different from those exhibited by CFTR purified under conditions that retain associated lipids native to the membrane. It was found that CFTR purified together with phospholipids and cholesterol using amphipol: A8-35, exhibited higher rates of catalytic activity, phosphorylation dependent channel activation and potentiation by the therapeutic compound, ivacaftor, than did CFTR purified in detergent. The catalytic activity of phosphorylated CFTR detergent micelles was rescued by the addition of phospholipids plus cholesterol, but not by phospholipids alone, arguing for a specific role for cholesterol in modulating this function. In summary, these studies highlight the importance of lipid interactions in the intrinsic activities and pharmacological potentiation of CFTR.},
	keywords = {CATALYTIC ACTIVITY; membrane protein purification; amphipol:A8-35; intrinsic anion channel activity; proteoliposomal flux; functional reconstitution},
	year = {2019},
	eissn = {2073-4409},
	orcid-numbers = {Laselva, Onofrio/0000-0002-0237-4079}
}

@article{MTMT:30387986,
	title = {STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL.},
	url = {https://m2.mtmt.hu/api/publication/30387986},
	author = {Csanády, László and Vergani, Paola and Gadsby, David C},
	doi = {10.1152/physrev.00007.2018},
	journal-iso = {PHYSIOL REV},
	journal = {PHYSIOLOGICAL REVIEWS},
	volume = {99},
	unique-id = {30387986},
	issn = {0031-9333},
	abstract = {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.},
	year = {2019},
	eissn = {1522-1210},
	pages = {707-738},
	orcid-numbers = {Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:30658945,
	title = {Cystic Fibrosis: Emerging Understanding and Therapies},
	url = {https://m2.mtmt.hu/api/publication/30658945},
	author = {Rey, Michael M. and Bonk, Michael P. and Hadjiliadis, Denis},
	doi = {10.1146/annurev-med-112717-094536},
	journal-iso = {ANNU REV MED},
	journal = {ANNUAL REVIEW OF MEDICINE},
	volume = {70},
	unique-id = {30658945},
	issn = {0066-4219},
	abstract = {Cystic fibrosis (CF) is the most common life-limiting genetic disease in Caucasian patients. Continued advances have led to improved survival, and adults with CF now outnumber children. As our understanding of the disease improves, new therapies have emerged that improve the basic defect, enabling patient-specific treatment and improved outcomes. However, recurrent ex-acerbations continue to lead to morbidity and mortality, and new pathogens have been identified that may lead to worse outcomes. In addition, new complications, such as CF-related diabetes and increased risk of gastrointestinal cancers, are creating new challenges in management. For patients with end-stage disease, lung transplantation has remained one of the few treatment options, but challenges in identifying the most appropriate patients remain.},
	keywords = {C-REACTIVE PROTEIN; IN-VITRO; cystic fibrosis; QUALITY-OF-LIFE; LUNG TRANSPLANTATION; ANTIBIOTIC-TREATMENT; adult patients; GLUCOSE-INTOLERANCE; CFTR modification; ACUTE PULMONARY EXACERBATIONS; LUNG-FUNCTION DECLINE; CFTR POTENTIATOR},
	year = {2019},
	eissn = {1545-326X},
	pages = {197-210}
}

@article{MTMT:3287704,
	title = {Ion channels as targets to treat cystic fibrosis lung disease},
	url = {https://m2.mtmt.hu/api/publication/3287704},
	author = {Martin, SL and Saint-Criq, V and Hwang, TC and Csanády, László},
	doi = {10.1016/j.jcf.2017.10.006},
	journal-iso = {J CYST FIBROS},
	journal = {JOURNAL OF CYSTIC FIBROSIS},
	volume = {17},
	unique-id = {3287704},
	issn = {1569-1993},
	abstract = {Lung health relies on effective mucociliary clearance and innate immune defence mechanisms. In cystic fibrosis (CF), an imbalance in ion transport due to an absence of chloride ion secretion, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and a concomitant sodium hyperabsorption, caused by dyregulation of the epithelial sodium channel (ENaC), results in mucus stasis which predisposes the lungs to cycles of chronic infection and inflammation leading to lung function decline. An increased understanding of CFTR structure and function has provided opportunity for the development of a number of novel modulators targeting mutant CFTR however, it is important to also consider other ion channels and transporters present in the airways as putative targets for drug development. In this review, we discuss recent advances in CFTR biology which will contribute to further drug discovery in the field. We also examine developments to inhibit the epithelial sodium channel (ENaC) and potentially activate alternative chloride channels and transporters as a multi-tracked strategy to hydrate CF airways and restore normal mucociliary clearance mechanisms in a manner independent of CFTR mutation.},
	year = {2018},
	eissn = {1873-5010},
	pages = {S22-S27},
	orcid-numbers = {Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:30363065,
	title = {ABC Transporters in Dynamic Macromolecular Assemblies},
	url = {https://m2.mtmt.hu/api/publication/30363065},
	author = {Trowitzsch, S. and Tampé, R.},
	doi = {10.1016/j.jmb.2018.07.028},
	journal-iso = {J MOL BIOL},
	journal = {JOURNAL OF MOLECULAR BIOLOGY},
	volume = {430},
	unique-id = {30363065},
	issn = {0022-2836},
	keywords = {ANTIGEN PRESENTATION; review; human; Membrane Proteins; priority journal; nonhuman; electron microscopy; Protein Binding; quality control; PROTEIN FUNCTION; major histocompatibility complex; Adenosine Triphosphate; glycosylation; protein domain; ADAPTIVE IMMUNITY; ADAPTIVE IMMUNITY; X ray crystallography; protein structure; ABC transporter; major histocompatibility antigen class 1; chaperone; protein motif; protein hydrolysis; protein assembly; ER quality control; tapasin},
	year = {2018},
	eissn = {1089-8638},
	pages = {4481-4495}
}

@article{MTMT:26407981,
	title = {Molecular modelling and molecular dynamics of CFTR},
	url = {https://m2.mtmt.hu/api/publication/26407981},
	author = {Callebaut, Isabelle and Hoffmann, Brice and Lehn, Pierre and Mornon, Jean-Paul},
	doi = {10.1007/s00018-016-2385-9},
	journal-iso = {CELL MOL LIFE SCI},
	journal = {CELLULAR AND MOLECULAR LIFE SCIENCES},
	volume = {74},
	unique-id = {26407981},
	issn = {1420-682X},
	year = {2017},
	eissn = {1420-9071},
	pages = {3-22}
}

@article{MTMT:26573010,
	title = {Attenuation of Phosphorylation-dependent Activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Disease-causing Mutations at the Transmission Interface},
	url = {https://m2.mtmt.hu/api/publication/26573010},
	author = {Chin, Stephanie and Yang, Donghe and Miles, Andrew J and Eckford, Paul D W and Molinski, Steven and Wallace, B A and Bear, Christine E},
	doi = {10.1074/jbc.M116.762633},
	journal-iso = {J BIOL CHEM},
	journal = {JOURNAL OF BIOLOGICAL CHEMISTRY},
	volume = {292},
	unique-id = {26573010},
	issn = {0021-9258},
	abstract = {Cystic fibrosis transmembrane conductance regulator (CFTR) is a multidomain membrane protein that functions as a phosphorylation-regulated anion channel. The interface between its two cytosolic nucleotide binding domains and coupling helices conferred by intracellular loops extending from the channel pore domains has been referred to as a transmission interface and is thought to be critical for the regulated channel activity of CFTR. Phosphorylation of the regulatory domain of CFTR by protein kinase A (PKA) is required for its channel activity. However, it was unclear if phosphorylation modifies the transmission interface. Here, we studied purified full-length CFTR protein using spectroscopic techniques to determine the consequences of PKA-mediated phosphorylation. Synchrotron radiation circular dichroism spectroscopy confirmed that purified full-length wild-type CFTR is folded and structurally responsive to phosphorylation. Intrinsic tryptophan fluorescence studies of CFTR showed that phosphorylation reduced iodide-mediated quenching, consistent with an effect of phosphorylation in burying tryptophans at the transmission interface. Importantly, the rate of phosphorylation-dependent channel activation was compromised by the introduction of disease-causing mutations in either of the two coupling helices predicted to interact with nucleotide binding domain 1 at the interface. Together, these results suggest that phosphorylation modifies the interface between the catalytic and pore domains of CFTR and that this modification facilitates CFTR channel activation.},
	keywords = {PHOSPHORYLATION; SPECTROSCOPY; ion channel; Cystic fibrosis transmembrane conductance regulator (CFTR); synchrotron radiation circular dichroism; cysteine-mediated cross-linking},
	year = {2017},
	eissn = {1083-351X},
	pages = {1988-1999}
}

@article{MTMT:26409492,
	title = {Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants},
	url = {https://m2.mtmt.hu/api/publication/26409492},
	author = {Chin, Stephanie and Hung, Maurita and Bear, Christine E},
	doi = {10.1007/s00018-016-2388-6},
	journal-iso = {CELL MOL LIFE SCI},
	journal = {CELLULAR AND MOLECULAR LIFE SCIENCES},
	volume = {74},
	unique-id = {26409492},
	issn = {1420-682X},
	year = {2017},
	eissn = {1420-9071},
	pages = {57-66}
}

@article{MTMT:27095255,
	title = {Different Principles of ADP-Ribose-Mediated Activation and Opposite Roles of the NUDT9 Homology Domain in the TRPM2 Orthologs of Man and Sea Anemone},
	url = {https://m2.mtmt.hu/api/publication/27095255},
	author = {Kuehn, Frank and Kuehn, Cornelia and Lueckhoff, Andreas},
	doi = {10.3389/fphys.2017.00879},
	journal-iso = {FRONT PHYSIOL},
	journal = {FRONTIERS IN PHYSIOLOGY},
	volume = {8},
	unique-id = {27095255},
	year = {2017},
	eissn = {1664-042X}
}

@article{MTMT:3210856,
	title = {Molecular Structure of the Human CFTR Ion Channel},
	url = {https://m2.mtmt.hu/api/publication/3210856},
	author = {Liu, F and Zhang, Z and Csanády, László and Gadsby, DC and Chen, J},
	doi = {10.1016/j.cell.2017.02.024},
	journal-iso = {CELL},
	journal = {CELL},
	volume = {169},
	unique-id = {3210856},
	issn = {0092-8674},
	abstract = {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.},
	keywords = {ABC transporter; anion channel; human CFTR; cryo-EM},
	year = {2017},
	eissn = {1097-4172},
	pages = {85-95.e8},
	orcid-numbers = {Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:27095230,
	title = {Substrate Specificity of the FurE Transporter Is Determined by Cytoplasmic Terminal Domain Interactions},
	url = {https://m2.mtmt.hu/api/publication/27095230},
	author = {Papadaki, Georgia F and Amillis, Sotiris and Diallinas, George},
	doi = {10.1534/genetics.117.300327},
	journal-iso = {GENETICS},
	journal = {GENETICS},
	volume = {207},
	unique-id = {27095230},
	issn = {0016-6731},
	year = {2017},
	eissn = {1943-2631},
	pages = {1387-1400}
}

@article{MTMT:3287727,
	title = {Asymmetry of movements in CFTR's two ATP sites during pore opening serves their distinct functions},
	url = {https://m2.mtmt.hu/api/publication/3287727},
	author = {Sorum, Ben and Törőcsik, Beáta and Csanády, László},
	doi = {10.7554/eLife.29013},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {6},
	unique-id = {3287727},
	issn = {2050-084X},
	abstract = {CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, is opened by ATP binding to two cytosolic nucleotide binding domains (NBDs), but pore-domain mutations may also impair gating. ATP-bound NBDs dimerize occluding two nucleotides at interfacial binding sites; one site hydrolyzes ATP, the other is inactive. The pore opens upon tightening, and closes upon disengagement, of the catalytic site following ATP hydrolysis. Extent, timing, and role of non-catalytic-site movements are unknown. Here we exploit equilibrium gating of a hydrolysis-deficient mutant and apply Phi value analysis to compare timing of opening-associated movements at multiple locations, from the cytoplasmic ATP sites to the extracellular surface. Marked asynchrony of motion in the two ATP sites reveals their distinct roles in channel gating. The results clarify the molecular mechanisms of functional cross-talk between canonical and degenerate ATP sites in asymmetric ABC proteins, and of the gating defects caused by two common CF mutations.},
	year = {2017},
	eissn = {2050-084X},
	orcid-numbers = {Sorum, Ben/0000-0001-6742-1094; Törőcsik, Beáta/0000-0002-9838-3710; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:26363440,
	title = {Exploring conformational equilibria of a heterodimeric ABC transporter},
	url = {https://m2.mtmt.hu/api/publication/26363440},
	author = {Timachi, MH and Hutter, CAJ and Hohl, M and Assafa, T and Böhm, S and Mittal, A and Seeger, MA and Bordignon, E},
	doi = {10.7554/eLife.20236},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {6},
	unique-id = {26363440},
	issn = {2050-084X},
	year = {2017},
	eissn = {2050-084X}
}