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5-methyl-dCTP + H2O + closed Cl- channel
5-methyl-dCDP + phosphate + open Cl- channel
-
-
-
?
7-methyl-GTP + H2O + closed Cl- channel
7-methyl-GDP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
ATP + H2O + closed I- channel
ADP + phosphate + open I- channel
-
-
-
-
?
CTP + H2O + closed Cl- channel
CDP + phosphate + open Cl- channel
-
-
-
?
dATP + H2O + closed Cl- channel
dADP + phosphate + open Cl- channel
-
-
-
?
dCTP + H2O + closed Cl- channel
dCDP + phosphate + open Cl- channel
-
-
-
?
dGTP + H2O + closed Cl- channel
dGDP + phosphate + open Cl- channel
-
-
-
?
dTTP + H2O + closed Cl- channel
dTDP + phosphate + open Cl- channel
-
-
-
?
dUTP + H2O + closed Cl- channel
dUDP + phosphate + open Cl- channel
-
-
-
?
GTP + H2O + closed Cl- channel
GDP + phosphate + open Cl- channel
TTP + H2O + closed Cl- channel
TDP + phosphate + open Cl- channel
-
-
-
?
UTP + H2O + closed Cl- channel
UDP + phosphate + open Cl- channel
-
-
-
?
additional information
?
-
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
654515, 654536, 654579, 654722, 655993, 656427, 674414, 675176, 699787, 700296, 700965, 719248, 749931, 749957, 750068, 750275, 750278, 750279, 750284, 750504, 750505, 750519, 751062, 751065, 751395 -
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
chloride channel
210420, 210421, 210422, 210423, 210424, 210425, 210426, 210427, 210428, 210429, 210430, 210431, 210432, 210433, 210434, 210435 -
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
sequence differences in the first membrane-spanning domains in human and Xenopus sp. are responsible for the differences in the permeation properties of human and Xenopus CFTR, the first extracellular loop influences channel gating
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
coupling between ATP hydrolysis and chloride channel gating
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a multiion-pore
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
dysfunction of CFTR causes the genetic disease cystic fibrosis
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the chloride channel is regulated by phosphorylation of the R domain and ATP hydrolysis at two nucleotide binding domains
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
transport of Cl-, I-, and with lower efficiency Br- and F-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR function in epithelial cells is regulated by an interplay between syntaxin and Munc18 isoforms
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
syntaxin 1A limits the functional activities of normal and disease-associated forms of the chloride channel
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR appears to be important both as a HCO3- conductance and also in some way as a direct or indirect regulator of adjacent anion exchange, e.g. as a source of luminal Cl- that may exchange for cellular HCO3- and/or as a means of keeping cellular Cl- concentration low enough that the anion exchanger operates as an HCO3- secretion mechanism
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
enzyme is regulated by cAMP
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
small-conductance chloride channel, direct coupling between cellular ATP levels and chloride channel activity may be an adaptive mechanism to protect the tissue from damage resulting from excessive energy depletion
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
can function as a chloride-selective anion channel, may also play a role in regulation of the membrane vesicle trafficking and fusion, acidification of organelles and transport of small anions
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a conductance regulator as well as a Cl- channel, CFTR regulates other ion channel proteins
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a conductance regulator as well as a Cl- channel, CFTR regulates other ion channel proteins
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
mediates transepithelial salt and lipid movement in the apical membrane of epithelia
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
malfunction of CFTR causes cystic fibrosis
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
malfunction of CFTR causes cystic fibrosis
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
ATPase that functions as a Cl- channel in which bursts of opening separate relatively long inburst closed times. ATP must bind at both catalytic sites before a CFTR channel can open. The opening is rate limiting by a slow step after binding that is rate limited by a slow step after binding that is sensitive to the structure of the polyphosphate chaIN: No further nucleotide binding to the open channel. Hydrolysis at nucleotide binding domain 2 preceds normal rapid channel closing. The integrity of the nucleotide binding domain 1 Walker A motif, and nucleotide bound there, influences the rate of exit from locked-open burst states
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme functions in vivo as a cAMP-activated chloride channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme normally functions as a phosphorylation-regulated chloriode channel on the apical surface of epithelial cells, and lack of this function is the primary cause for the fatal disease cystic fibrosis
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
protein kinase A phosphorylates a group of R-domain serine residues in nucleotide binding domain 1. This causes the fusion protein to dimerize, to exhibit cooperative ATP binding and hydrolysis, and to be subject to regulation by nucleotide binding domain 2
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the NBF1+R segment (nucleotide binding domain 1 and regulatory domain) has the capacity to catalyze ATP hydrolysis in the absence of a fusion partner
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
ATP binding induces a modest conformational change in the sixth transmembrane segment, and this conformational change is coupled to the gating mechanism that regulates ion conduction
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR acts as an ATP-dependent chloride channel. CFTR channel activity evolved, at least in part, by converting the conformational changes associated with binding and hydrolysis of ATP
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR functions as an ATP-gated Cl- channel that is critical for proper hydration of the mucosal layer that lines lung airways. Individuals who inherit two mutant forms of CFTR have exceedingly viscous mucous and, due to chronic lung infections, develop cystic fibrosis and often die from lung failure
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
CFTR is a chloride channel whose dysfunction causes cystic fibrosis. The two intracellular nucleotide-binding domains of CFTR control the opening and closing of the channel, structure modelling of the CFTRs NBD1-NBD2 complex using the NBD crystal structures, overview
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a Cl- channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR shares a common molecular mechanism with other members of the ATP-binding cassette superfamily. CFTR gating is regulated by protein kinase A-mediated phosphorylation and by interaction with ATP
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme also shows ion channel activity
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
analysis of the dynamic events involved in the allosteric regulation of CFTR function, role of ATP hydrolysis in CFTR function, CFTR channel gating is a reversible thermally driven process with all structural reorganization in the binding site(s) completed prior to channel opening, requirement for nucleotide binding for channel opening, overview
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
ATP binding, at one or both nucleotide binding sites, occurs on closed channels and is required for channel opening. ATP binds to partial binding sites on the surface of the two nucleotide binding sites, NBDs, which then associate to form a NBD dimer, with complete composite catalytic sites now buried at the interface. After ATP binding, formation of a tight NBD1/NBD2 dimer is coupled to conformational changes in the transmembrane domains opening the diffusion pathway for anions. Hydrolysis at the consensus site allows fast channel closure, controlled by NBD dimerization, overview
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
binding mode of ATP in the CFTR nucleotide-binding domain NBD1-NBD2 dimer, organisation of the ATP-binding sites in CFTR involving Walker A and B motifs, and the signature sequence LSGGQ, and conformational changes of the CFTR Cl- channel during channel gating, overview
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
binding mode of ATP in the CFTR nucleotide-binding domain NBD1-NBD2 dimer: residue W401 of NBD1 forms ring-ring stacking with the adenine ring of ATP, residues at the NBD2 site that exhibit hydrogen bonding with the second ATP molecule include G1247, S1248, K1250, S1251, T1252 of the Walker A motif of NBD2, Q1291 of the Q-loop of NBD2, T547, S549, and G551 of the signature motif of NBD1. D1370 and E1371 of the Walker B of NBD2 coordinate MgATP, while Y1219 of NBD2 coordinates the adenine ring of ATP through ring-ring stacking
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
Mg2+-dependent ATP occlusion at the first nucleotide-binding domain, NBD1, of CFTR does not require the second, NBD2. ATP binding to the first and second NBDs of CFTR are bivalent-cation-independent and -dependent steps, respectively
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
stable binding of ATP at nucleotide binding site NBD1 and binding and hydrolysis of ATP at NBD2, together with R domain phosphorylation, may alter allosteric interactions between these domains and impact the channel gating cycle
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the Walker A and the Walker B motifs together with the signature sequence LSGGQ form the ATP-binding pocket upon dimerization of the two nucleotide-binding domains in a head-to-tail configuration
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
ATP binding gates open enzyme CFTR by an allosteric mechanism, ATP binding biases the equilibrium toward the CFTR open state but is not absolutely required for channel opening
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
using inside-out membrane patches from HeLa cells recombinantly and transiently expressing either wild-type or mutant enzyme CFTR
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
ATP in form of MgATP2-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
chloride channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme is an ATP-binding cassette transporter that functions as a chloride channel. Channel gating occurs through ATP binding in an nucleotide-binding domain 1-nucleotide-binding domain 2 nucleotide sandwich that forms upon displacement of nucleotide-binding domain 1 regulatory segments
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a Cl- channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
chloride channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
EBCR is involved in hormone-regulated chloride reabsorption
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
ATPase activity is much higher at NBD1 than NBD2 of CFTR, ATPase activity is not strictly required for its channel activity
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
shark
-
chloride channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
anion permeability sequence: Br- = I-, Cl-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
chloride channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
sequence differences in the first membrane-spanning domains in human and Xenopus sp. are responsible for the differences in the permeation properties of human and Xenopus CFTR, the first extracellular loop influences channel gating
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
anion permeability sequence: Br- = Cl-, I-
-
-
?
GTP + H2O + closed Cl- channel
GDP + phosphate + open Cl- channel
-
-
-
-
?
GTP + H2O + closed Cl- channel
GDP + phosphate + open Cl- channel
-
-
-
?
additional information
?
-
-
the cystic fibrosis transmembrane conductance regulator normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cell, and lack of this function is the primary cause for the fatal disease cystic fibrosis
-
-
?
additional information
?
-
CFTR protein channel requires phosphorylation by PKA before they can be opened by ATP, close upon ATP removal, and are activated half-maximally by 0.05 mM ATP
-
-
?
additional information
?
-
-
the isolated nucleotide-binding domains exhibit adenylate kinase activity, while the full-length purified and reconstituted protein functions as a ATPase
-
-
?
additional information
?
-
-
a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator results in abnormal electrolyte permeability in various exocrine epithelia causing cystic fibrosis, one of the most common lethal autosomal recessive disorders in Caucasian populations
-
-
?
additional information
?
-
-
cAMP-dependent on for Cl- conductance, no concurrent activation of K+ conductance. CFTR defects abolishes beta-adrenergic response of sweat gland and sweating in cystic fibrosis, but not cholinergic sweating, overview
-
-
?
additional information
?
-
-
cytosolic 70-kDa heat shock protein and endoplasmic reticulum-localized calnexin are chaperones that facilitate CFTR biogenesis. Hsp70 functions in both the cotranslational folding and posttranslational degradation of CFTR
-
-
?
additional information
?
-
-
enzyme defects or inhibition lead to cystic fibrosis
-
-
?
additional information
?
-
-
neither channel activation nor inhibition influence the pH in recycling endosomes nor immature phagosomes. Perturbations of the endo-lysosomal organelles pH homeostasis cannot be linked to the etiology of the cystic fibrosis lung disease
-
-
?
additional information
?
-
-
the cystic fibrosis transmembrane conductance regulator is a unique ATP-binding cassette ion channel mutated in patients with cystic fibrosis
-
-
?
additional information
?
-
-
the enzyme acts as an ion channel, e.g. transporting chloride and the anionic cysteine-reactive reagents methanesulfonate sodium (2-sulfonatoethyl)methanesulfonate, organic mercurial 4-chloromercuriphenylsulfonic acid, and the permeant anion Au(CN)2-, but only in activated status, in nonactivated channels some ion selectivity mechanism exists to exclude anions yet permit cations into the channel pore from the extracellular solution. Activation of CFTR channels involves a conformational change in the pore that removes a strong selectivity against anion entry from the extracellular solution
-
-
?
additional information
?
-
-
the enzyme performs Cl- conductance. Chaperones Hsp70 and Hsp90 associate equally with wild-type and mutant DELTAF508 CFTR, whereas nearly twice as much of the Hsp90 cochaperone, Aha1, associates with mutant DELTAF508 CFTR
-
-
?
additional information
?
-
-
wild-type CFTR functions as a cAMP-activated chloride channel that has an important role in ion transport across the apical surfaces of secretory epithelia, also requiring caveolin-1 spatially associated to CFTR. Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa in lungs. The cells reaction involves the rapid formation of detergent-resistant membrane microdomains, i.e. lipid rafts, containing CFTR. Enzyme defects lead to defective innate immunity and susceptibility to chronic lung infection with Pseudomonas aeruginosa in cystic fibrosis patients, overview
-
-
?
additional information
?
-
-
an ATPase cycle involving formation and dissociation of tight nucleotide binding dimers drives the cyclical conformational changes in the transmembrane domains resulting in uphill allocrite transport, via ATP binding, tight NBD dimerization, hydrolysis, loss of the gamma-phosphate, and opening of the NBD-NBD interface
-
-
?
additional information
?
-
-
mechanism of action of small molecules that modulate CFTR channel gating
-
-
?
additional information
?
-
-
the enzyme performs Cl- conductance
-
-
?
additional information
?
-
-
the enzyme shows ATPase and chloride channel activities
-
-
?
additional information
?
-
-
a stable binding of ATP to NBD2 is required forthe normal, fast gating cycle of CFTR channel, and instability of ATP binding frequently halts the CFTR gating cycle in the open state presumably through a slowdown of ATP hydrolysis at NBD2
-
-
?
additional information
?
-
cystic fibrosis transmembrane conductance regulator (CFTR) channels have ATPase and adenylate kinase activity. In presence of ATP and physiologically relevant concentrations of AMP, the enzyme exhibits adenylate kinase activity, converting ATP and AMP into 2 ADP and vice versa. The enzyme interacts with AMP in an ATP-dependent manner
-
-
?
additional information
?
-
-
cystic fibrosis transmembrane conductance regulator (CFTR) channels have ATPase and adenylate kinase activity. In presence of ATP and physiologically relevant concentrations of AMP, the enzyme exhibits adenylate kinase activity, converting ATP and AMP into 2 ADP and vice versa. The enzyme interacts with AMP in an ATP-dependent manner
-
-
?
additional information
?
-
two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, are required for normal channel function, cooperation mode to maintain the open pore architecture of the enzyme, overview. Arg347 not only interacts with Asp924 but also interacts with Asp993. Arg347 forms a salt bridge with Asp924 but does not stabilize the full open state. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge
-
-
?
additional information
?
-
-
two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, are required for normal channel function, cooperation mode to maintain the open pore architecture of the enzyme, overview. Arg347 not only interacts with Asp924 but also interacts with Asp993. Arg347 forms a salt bridge with Asp924 but does not stabilize the full open state. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge
-
-
?
additional information
?
-
in the presence of ATP and physiologically relevant concentrations of AMP, the enzyme exhibits adenylate kinase activity, converting ATP and AMP into 2 ADP and vice versa. The interaction of nucleotide triphosphate with the enzyme at ATP-binding site 2 is required for this activity. ATP and AMP interact with separate binding sites but mutually influence their interaction with the ABC adenylate kinase CFTR, the active center of the adenylate kinase comprises ATP-binding site 2
-
-
?
additional information
?
-
-
enzyme defects or inhibition lead to cystic fibrosis
-
-
?
additional information
?
-
-
neither channel activation nor inhibition influence the pH in recycling endosomes nor immature phagosomes. Perturbations of the endo-lysosomal organelles pH homeostasis cannot be linked to the etiology of the cystic fibrosis lung disease, effect of CFTR deficiency in genetically matched respiratory epithelia and alveolar macrophages, overview. CFTR-independent endosomal and phagosomal acidification occurs in RAW macrophages
-
-
?
additional information
?
-
ATP gates ovine CFTR with greater affinity and efficacy than human CFTR
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
ATP + H2O + closed I- channel
ADP + phosphate + open I- channel
-
-
-
-
?
additional information
?
-
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
654515, 654536, 655993, 699787, 749931, 749957, 750068, 750275, 750278, 750279, 750284, 750504, 750505, 750519, 751062, 751065, 751395 -
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
coupling between ATP hydrolysis and chloride channel gating
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR function in epithelial cells is regulated by an interplay between syntaxin and Munc18 isoforms
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
syntaxin 1A limits the functional activities of normal and disease-associated forms of the chloride channel
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR appears to be important both as a HCO3- conductance and also in some way as a direct or indirect regulator of adjacent anion exchange, e.g. as a source of luminal Cl- that may exchange for cellular HCO3- and/or as a means of keeping cellular Cl- concentration low enough that the anion exchanger operates as an HCO3- secretion mechanism
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
enzyme is regulated by cAMP
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
small-conductance chloride channel, direct coupling between cellular ATP levels and chloride channel activity may be an adaptive mechanism to protect the tissue from damage resulting from excessive energy depletion
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
can function as a chloride-selective anion channel, may also play a role in regulation of the membrane vesicle trafficking and fusion, acidification of organelles and transport of small anions
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a conductance regulator as well as a Cl- channel, CFTR regulates other ion channel proteins
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a conductance regulator as well as a Cl- channel, CFTR regulates other ion channel proteins
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
mediates transepithelial salt and lipid movement in the apical membrane of epithelia
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
malfunction of CFTR causes cystic fibrosis
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
malfunction of CFTR causes cystic fibrosis
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
ATPase that functions as a Cl- channel in which bursts of opening separate relatively long inburst closed times. ATP must bind at both catalytic sites before a CFTR channel can open. The opening is rate limiting by a slow step after binding that is rate limited by a slow step after binding that is sensitive to the structure of the polyphosphate chaIN: No further nucleotide binding to the open channel. Hydrolysis at nucleotide binding domain 2 preceds normal rapid channel closing. The integrity of the nucleotide binding domain 1 Walker A motif, and nucleotide bound there, influences the rate of exit from locked-open burst states
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme functions in vivo as a cAMP-activated chloride channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme normally functions as a phosphorylation-regulated chloriode channel on the apical surface of epithelial cells, and lack of this function is the primary cause for the fatal disease cystic fibrosis
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR acts as an ATP-dependent chloride channel. CFTR channel activity evolved, at least in part, by converting the conformational changes associated with binding and hydrolysis of ATP
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR functions as an ATP-gated Cl- channel that is critical for proper hydration of the mucosal layer that lines lung airways. Individuals who inherit two mutant forms of CFTR have exceedingly viscous mucous and, due to chronic lung infections, develop cystic fibrosis and often die from lung failure
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
CFTR is a chloride channel whose dysfunction causes cystic fibrosis. The two intracellular nucleotide-binding domains of CFTR control the opening and closing of the channel, structure modelling of the CFTRs NBD1-NBD2 complex using the NBD crystal structures, overview
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a Cl- channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR shares a common molecular mechanism with other members of the ATP-binding cassette superfamily. CFTR gating is regulated by protein kinase A-mediated phosphorylation and by interaction with ATP
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme also shows ion channel activity
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme is an ATP-binding cassette transporter that functions as a chloride channel. Channel gating occurs through ATP binding in an nucleotide-binding domain 1-nucleotide-binding domain 2 nucleotide sandwich that forms upon displacement of nucleotide-binding domain 1 regulatory segments
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a Cl- channel
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
EBCR is involved in hormone-regulated chloride reabsorption
-
?
additional information
?
-
-
the cystic fibrosis transmembrane conductance regulator normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cell, and lack of this function is the primary cause for the fatal disease cystic fibrosis
-
-
?
additional information
?
-
-
a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator results in abnormal electrolyte permeability in various exocrine epithelia causing cystic fibrosis, one of the most common lethal autosomal recessive disorders in Caucasian populations
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-
?
additional information
?
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-
cAMP-dependent on for Cl- conductance, no concurrent activation of K+ conductance. CFTR defects abolishes beta-adrenergic response of sweat gland and sweating in cystic fibrosis, but not cholinergic sweating, overview
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-
?
additional information
?
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-
cytosolic 70-kDa heat shock protein and endoplasmic reticulum-localized calnexin are chaperones that facilitate CFTR biogenesis. Hsp70 functions in both the cotranslational folding and posttranslational degradation of CFTR
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-
?
additional information
?
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-
enzyme defects or inhibition lead to cystic fibrosis
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-
?
additional information
?
-
-
neither channel activation nor inhibition influence the pH in recycling endosomes nor immature phagosomes. Perturbations of the endo-lysosomal organelles pH homeostasis cannot be linked to the etiology of the cystic fibrosis lung disease
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-
?
additional information
?
-
-
the cystic fibrosis transmembrane conductance regulator is a unique ATP-binding cassette ion channel mutated in patients with cystic fibrosis
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-
?
additional information
?
-
-
the enzyme acts as an ion channel, e.g. transporting chloride and the anionic cysteine-reactive reagents methanesulfonate sodium (2-sulfonatoethyl)methanesulfonate, organic mercurial 4-chloromercuriphenylsulfonic acid, and the permeant anion Au(CN)2-, but only in activated status, in nonactivated channels some ion selectivity mechanism exists to exclude anions yet permit cations into the channel pore from the extracellular solution. Activation of CFTR channels involves a conformational change in the pore that removes a strong selectivity against anion entry from the extracellular solution
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-
?
additional information
?
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-
the enzyme performs Cl- conductance. Chaperones Hsp70 and Hsp90 associate equally with wild-type and mutant DELTAF508 CFTR, whereas nearly twice as much of the Hsp90 cochaperone, Aha1, associates with mutant DELTAF508 CFTR
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-
?
additional information
?
-
-
wild-type CFTR functions as a cAMP-activated chloride channel that has an important role in ion transport across the apical surfaces of secretory epithelia, also requiring caveolin-1 spatially associated to CFTR. Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa in lungs. The cells reaction involves the rapid formation of detergent-resistant membrane microdomains, i.e. lipid rafts, containing CFTR. Enzyme defects lead to defective innate immunity and susceptibility to chronic lung infection with Pseudomonas aeruginosa in cystic fibrosis patients, overview
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-
?
additional information
?
-
cystic fibrosis transmembrane conductance regulator (CFTR) channels have ATPase and adenylate kinase activity. In presence of ATP and physiologically relevant concentrations of AMP, the enzyme exhibits adenylate kinase activity, converting ATP and AMP into 2 ADP and vice versa. The enzyme interacts with AMP in an ATP-dependent manner
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-
?
additional information
?
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-
cystic fibrosis transmembrane conductance regulator (CFTR) channels have ATPase and adenylate kinase activity. In presence of ATP and physiologically relevant concentrations of AMP, the enzyme exhibits adenylate kinase activity, converting ATP and AMP into 2 ADP and vice versa. The enzyme interacts with AMP in an ATP-dependent manner
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-
?
additional information
?
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two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, are required for normal channel function, cooperation mode to maintain the open pore architecture of the enzyme, overview. Arg347 not only interacts with Asp924 but also interacts with Asp993. Arg347 forms a salt bridge with Asp924 but does not stabilize the full open state. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge
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-
?
additional information
?
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-
two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, are required for normal channel function, cooperation mode to maintain the open pore architecture of the enzyme, overview. Arg347 not only interacts with Asp924 but also interacts with Asp993. Arg347 forms a salt bridge with Asp924 but does not stabilize the full open state. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge
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-
?
additional information
?
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-
enzyme defects or inhibition lead to cystic fibrosis
-
-
?
additional information
?
-
-
neither channel activation nor inhibition influence the pH in recycling endosomes nor immature phagosomes. Perturbations of the endo-lysosomal organelles pH homeostasis cannot be linked to the etiology of the cystic fibrosis lung disease, effect of CFTR deficiency in genetically matched respiratory epithelia and alveolar macrophages, overview. CFTR-independent endosomal and phagosomal acidification occurs in RAW macrophages
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?
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2-(pyridin-4-yl)-4H-benzo[h]chromen-4-one
-
i.e. UCCF-029. Concentrations below 50 nM increase the open probability of the channel, favouring the channel transition to the an activated state. Levels above 50 nM determine inhibition of the channel by a reduction of the open time. UCCF-029 does not interfere with binding of ATP
2-sulfonatoethyl methanethiosulfonate
enzyme residues A299, R303, N306, S307, F310, and F311 are accessible to intracellular 2-sulfonatoethyl methanethiosulfonate in both the open and closed states
3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone
-
CFTR(inh)-172, potent CFTR inhibitor, exerts nonspecific effects regarding reactive oxygen species production, mitochondrial failure, and activation of the NF-kappa B signaling pathway, independently of CFTR inhibition
5-nitro-2(3-phenylpropylamino)benzoate
-
-
5-nitro-2-(3-phenylpropylamine)benzoic acid
-
-
5-[(4-carboxyphenyl)methylene]-2-thioxo-3-[(3-trifluoromethyl)phenyl]4-thiazolidinone
-
-
8-(4-chlorophenylthio)-AMP
-
the ATPase activity of the enzyme is reduced in the presence of higher concentrations of 8-(4-chlorophenylthio)-AMP
8-azido-ATP
-
is retained at nucleotide-binding domain 1, NBD1 at low temperature even in the absence of bivalent cations
adenylyl-imidodiphosphate
-
modulation of the on-rate of venom binding for intraburst block
adenylyliminodiphosphate
-
-
Antibody
-
inhibits CFTR, alleviation of ovarian hyperstimulation syndrome symptoms
-
ATP-P3-[1-(2-nitrophenyl)ethyl]ester
-
-
Au(CN)2-
-
inhibits the ion channel function
CL1 peptide
-
both intrinsic ATPase activity and channel gating are inhibited severely by CL1 peptide
-
detergent SB-300
-
blocks forskolin-stimulated CFTR Cl- secretion by 92.2%
-
detergent SB-303
-
decreases stimulated CFTR Cl- currents by 98%
-
diphenylamine-2,2'-dicarboxylic acid
-
fully inhibits
diphenylamine-2-carboxylate
-
-
Fe3+
binds at the interface of the regulatory (R) domain and intracellular loop (ICL) 3
forskolin
abolishes the enzyme activity, which is reversible by DTT
genistein
bindings of genistein and ATP are competitive
glibencalmide
an open-channel blocker
HgCl2
-
dose-dependent inhibition of forskolin/3-isobutyl-1-methylxanthine-stimulated chloride secretion, inhibition is maximal when HgCl2 is added before stimulation with forskolin/3-isobutyl-1-methylxanthine, dithiothrietol and glutathione completely prevent inhibition of chloride secretion, inhibits chloride secretion by interacting with the apical membrane
N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide
-
GlyH-101, potent CFTR inhibitor, exerts nonspecific effects regarding reactive oxygen species production, mitochondrial failure, and activation of the NF-kappa B signaling pathway, independently of CFTR inhibition
N6-(2-phenylethyl)-ATP
competitive with ATP, binds to ATP-binding pocket 1
P1,P5-di(adenosine-5') pentaphosphate
Ap5A, an adenylate kinase inhibitor that partially inhibits wild-type CFTR, and inhibition can be attenuated by high ATP concentrations
phosphatidylinositol 4,5-bisphosphate
-
applied to phosphorylated CTFR may inhibit the CTFR chloride current
progesterone
-
supresses CFTR expression, alleviation of ovarian hyperstimulation syndrome symptoms
venom
-
from Leirus quinquestriatus hebraeus, reversly inhibits CFTR, when applied to its cytoplasmic surface, preferentially binds to closed CFTR channels, effectiveness of macroscopic inhibition depends on the level of CFTR channel activity, the venom also binds to CFTR during intraburst closings, efficacy of intraburst inhibition at the single-channel level depends on open probability
-
VRT-532
-
i.e. 4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)-phenol, the ATPase activity of the purified and reconstituted mutant DELTAPhe508-CFTR is directly modulated and ATP turnover is decreased by binding of VRT-532, but VRT-532 stimulates channel function of DELTAPhe508-CFTR in cells. VRT-532 binding induces a change in conformational stability of the C-terminal half of DELATPhe508-CFTR
Zn2+
-
Zn2+ inhibits channel activity in a dose- and Cl--dependent manner. Cl--dependent Zn2+ inhibition is weakened at higher Zn2+ concentrations, Zn2+ affinity is stronger in the resting state than in the activated state, and activation current noises are decreased by external Zn2+ binding
CFTRinh-172
-
inhibits cAMP stimulated but not basal fluid transport
CFTRinh-172
-
possibly inhibits CFTR currents by alteration of gating mechanisms
CFTRinh-172
-
a specific CFTR inhibitor, inhibits ATPase activity of mutant DELTAPhe508-CFTR
CFTRinh-172
-
specific inhibitor
CFTRinh-172
-
i.e., 5-[(4-carboxyphenyl)methylene]-2-thioxo-3-[(3-trifluoromethyl)phenyl]4-thiazolidinone
CFTRinh-172
-
specific inhibitor
CFTRinh-172
-
acidosis-induced ATP efflux from the perfused muscle is abolished by inhibitor CFTRinh-172
glibenclamide
-
-
glibenclamide
-
fully inhibits
glibenclamide
an open-channel blocker
glybenclamide
-
-
GlyH-101
-
specific inhibitor
GlyH-101
-
specific inhibitor
GSH
-
-
GSH
-
10 mM, 39% inhibition of wild-type enzyme, 63% inhibition of mutant enzyme R347D
vanadate
-
-
vanadate
-
modulation of the on-rate of venom binding for intraburst block
[Au(CN)2]-
a channel-permeant thiol-specific reagent
[Au(CN)2]-
reversible blocking effect of [Au(CN)2]- on enzyme CFTR
additional information
-
diphenylamine-2-carboxylate shows no state-dependence of block
-
additional information
-
anion binding makes the Cl-channel pore susceptible to inhibitors
-
additional information
-
no inhibition of CFTR by CdCl2
-
additional information
-
4,4'-diisothiocyano-2,29-stilbenedisulfonic acid and tamoxifen have little effect on enzyme activity
-
additional information
-
not inhibited by calixarene
-
additional information
inhibition of the enzyme with inhibitor CFTRinh172 and transfection with CFTR-specific siRNAs in DC2 cells reduces basal and forskolin-activated ATP release
-
additional information
-
4,4'-diisothiocyano-2,29-stilbenedisulfonic acid and tamoxifen have little effect on enzyme activity
-
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1,3-diallyl-8-cyclohexylxanthine
-
-
17beta-estradiol
-
potentiates the isoprenaline-induced chloride current, can also potentiate the chloride current if conjugated to bovine serum albumin, has no effect in the absence of isoprenaline, potentiation is partially blocked by NO synthase inhibition
2-(pyridin-4-yl)-4H-benzo[h]chromen-4-one
-
i.e. UCCF-029. Concentrations below 50 nM increase the open probability of the channel, favouring the channel transition to the an activated state. Levels above 50 nM determine inhibition of the channel by a reduction of the open time. UCCF-029 does not interfere with binding of ATP
2-pyrimidin-7,8-benzoflavone
-
induces significant conformational changes of the isolated NBD1/NBD2 dimer in solution. 2-pyrimidin-7,8-benzoflavone does not modify the ATP binding constant, but reduces the ATP hydrolysis activity of the NBD1/NBD2 mixture. In absence of ATP, the NBD1/NBD2 dimer is disrupted by the compound, but in the presence of 2 mM ATP, the two NBDs keep dimerised, and a major change in the size and the shape of the structure is observed
3-isobutyl-1-methylxanthine
3-isobutyl-methylxanthine
-
-
5-hydroxytryptamine
-
activates CFTR in myocytes
8-(4-chlorophenylthio)-AMP
-
the ATPase activity of the enzyme is enhanced in the presence of very low concentrations of 8-(4-chlorophenylthio)-AMP
8-cyclopentyl-1,3-dipropylxanthine
-
activates prephosphorylated CFTR by binding directly to CFTR
ATP
half-maximal activation by 0.05 mM
BeF3
-
amount of Cl- currents is less than 30% that of the wild-type CFTR
benzimidazolone compounds
-
-
-
benzoquinolizinium compounds
-
-
-
calnexin
-
Dependence on calnexin for proper assembly of CFTRs membrane spanning domains exists, also efficient folding of NBD2 is dependent upon calnexin binding to CFTR, but calnexin is not essential for wild-type CFTR or mutant CFTR DELTAF508 degradation
-
curcumin
molecular basis for Fe(III)-independent curcumin potentiation of cystic fibrosis transmembrane conductance regulator activity, overview. Highly conserved aromatic and positively charged residues at the ICL1/ICL4 interface and phosphorylation site S813 are sensitive to curcumin regardless of whether Fe3+ and nucleotide-binding domain 2 are removed. Spontaneous disulfide cross-linking between curcumin-sensitive ICL1 and S795 is observed to be enough to promote channel opening as curcumin does. Curcumin may potentiate CFTR activity not only by removing inhibitory Fe3+ to release the R domain from ICL3 but also by stabilizing the stimulatory R-ICL1/ICL4 interactions
estrogen
-
high amounts upregulate CFTR expression
fluorescein derivative
-
-
-
isoprenaline
-
induces the chloride current
KCN
-
without cAMP stimulation, KCN treatment increases CFTR Cl- conductance by 1.95fold, whereas after cAMP stimulation KCN treatment increases conductance by 13.7fold
NS-004
-
activates prephosphorylated CFTR by binding directly to CFTR
phosphatidylinositol 4,5-bisphosphate
-
activation of CTFR, which results in ATP responsiveness, AtP opens nonphosphorylated CTFR after application of phosphatidylinositol 4,5-bisphosphate
phosphatidylserine
-
the enzyme requires phosphatidylserine for maximum ATPase activity
Vasoactive intestinal peptide
-
stimulates
VO43-
-
prolongs the duration of the burst of channel activity
VRT-532
-
i.e. 4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)-phenol, the ATPase activity of the purified and reconstituted mutant DELTAPhe508-CFTR is directly modulated and ATP turnover is decreased by binding of VRT-532, but VRT-532 stimulates channel function of DELTAPhe508-CFTR in cells. VRT-532 binding induces a change in conformational stability of the C-terminal half of DELATPhe508-CFTR
3-isobutyl-1-methylxanthine
-
-
3-isobutyl-1-methylxanthine
-
activates
3-isobutyl-1-methylxanthine
-
CFTR activation, together with forskolin
3-isobutyl-1-methylxanthine
-
-
cAMP
-
activates
cAMP
-
dependent on for Cl- conductance, no concurrent activation of K+ conductance
cAMP
-
stimulates the ion channel function
diphosphate
-
amount of Cl- currents is less than 30% that of the wild-type CFTR
diphosphate
-
activates the enzyme ion channel
forskolin
-
-
forskolin
-
CFTR activation, together with 3-isobutyl-1-methylxanthine
forskolin
-
stimulates Cl- currents
forskolin
-
lubiprostone and forskolin activate the same pool of apical Cl- channels
forskolin
-
stimulates, potentiation in the presence of genistein
genistein
-
activates prephosphorylated CFTR by binding directly to CFTR, higher concentrations inhibit
genistein
-
stimulates, potentiation in the presence of forskolin
isoproterenol
-
-
isoproterenol
-
stimulates
lubiprostone
-
lubiprostone and forskolin activate the same pool of apical Cl- channels, lubiprostone induces the secretory response in intestinal epithelium involving the enzyme. Lubiprostone enhances intestinal Cl- and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. The EP4-type prostanoid receptor antagonist L-161982 blocks the lubiprostone response. Lubiprostone enhances Cl- secretion across human large and mall intestinal epithelium through a CFTR-dependent pathway
lubiprostone
-
lubiprostone enhances Cl- secretion across mouse ileum through a CFTR-dependent pathway and induces the secretory response in intestinal epithelium involving the enzyme. Lubiprostone enhances intestinal Cl- and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. The EP4-type prostanoid receptor antagonist L-161982 blocks the lubiprostone response
additional information
-
milrinone stimulates CFTR by raising cAMP concentration
-
additional information
-
activation of the cAMP-dependent protein kinase causes the phosphorylation of multiple serine residues within the R domain of CFTR. Once the R domain is phosphorylated, channel gating is regulated by a cycle of ATP hydrolysis at the nucleotide-binding domains. Finally, protein phosphatases dephosphorylate the R domain and return the channel to its quiescent state
-
additional information
-
phosphorylation dependent and nucleotide-hydrolysis dependent gating of CFTR is directly involved in gating of an associated ATP channel
-
additional information
-
beta-adrenergic agonists isoproprenaline and salbutamol induce sweat secretion only when applied in combination with an adenylyl cyclase activator, i.e. forskolin, or a phosphodiesterase inhibitor, i.e. 3-isobutyl-1-methylxanhine, aminophylline, or theophylline
-
additional information
-
treatment of IB3-1 cells with an aminoglycoside, e.g. G-418 or gentamicin, increases levels of W1282X-CFTR mRNA, with increased production of CFTR due to read-through of the W1282X stop mutation and parallel induction of cAMP-dependent Cl- efflux in treated cells
-
additional information
adenosine 5'-(beta,gamma-imido)triphosphate, AMP-PNP, is a non-hydrolyzable ATP analogue that increases wild-type CFTR current by delaying channel closing and inducing prolonged open bursts
-
additional information
-
adenosine 5'-(beta,gamma-imido)triphosphate, AMP-PNP, is a non-hydrolyzable ATP analogue that increases wild-type CFTR current by delaying channel closing and inducing prolonged open bursts
-
additional information
phosphorylation-dependent enzyme activity
-
additional information
-
phosphorylation-dependent enzyme activity
-
additional information
-
the ATPase activity of the enzyme is enhanced by anion channel inhibitors including glibenclamide, glipizide, and CFTRinh-172
-
additional information
-
the channel activity of both wild type and G551D mutant enzyme is directly stimulated by mechanical perturbation induced by cell swelling at the single-channel, cellular, and tissue levels. The enzyme is also activated by membrane stretch
-
additional information
-
the channel activity of both wild type and G551D mutant enzyme is directly stimulated by mechanical perturbation induced by cell swelling at the single-channel, cellular, and tissue levels. The enzyme is also activated by membrane stretch
-
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metabolism
-
Hsc70 plays a crucial role in degradation of mutant CFTR by the ubiquitin-proteasome system. The small molecule apoptozole has high cellular potency to promote membrane trafficking of mutant DeltaF508 and its chloride channel activity in cystic fibrosis cells. Apoptozole inhibits the ATPase activity of Hsc70 by binding to its ATPase domain and apoptozole suppresses ubiquitination of DeltaF508 maybe by blocking interaction of the mutant with Hsc70 and E3 ubiquitin ligase CHIP, and, as a consequence, it enhances membrane trafficking of the mutant
evolution
ATP-binding cassette (ABC) transporters are an ancient family of transmembrane proteins that utilize ATPase activity to move substrates across cell membranes. The ABCC subfamily of the ABC transporters includes active drug exporters and a unique ATP-gated ion channel, the cystic fibrosis transmembrane conductance regulator. CFTR channels and MRP efflux pumps share a conserved allosteric mechanism for coupling ATP binding to the translocation pathway, and reinforce the view that the CFTR gating mechanism is similar to the activation mechanisms of conventional ligand-gated channels. A proline (Pro355) at the base of pore-lining transmembrane segment 6 in enzyme CFTR is well conserved among the ABCC subfamily of ABC transporters
evolution
the enzyme belongs to the ATP-binding cassette (ABC) protein superfamily, ABCC subfamily, contains mainly transporters responsible for a range of functions from nutrient uptake to toxin export and these proteins are found in all organisms ranging from bacteria to mammals. The CFTR gene is unique within the ATP-binding cassette (ABC) protein family, predominantly of transporters, by coding a chloride channel
evolution
the enzyme is a bona fide member of the ATP-binding cassette (ABC) transporter superfamily. The presence of a gate in enzyme CFTR at a segment that may also serve as the selectivity filter provides functional duality of a restrictive segment close to the middle of the pore axis distinguishes CFTR from other members of the ABC protein family
evolution
the enzyme is a member of the ATP-binding cassette (ABC) transporter superfamily, a class of membrane proteins that couple the hydrolysis ofATPwith the transport of molecules across membranes. The enzyme belongs to the ABC-C subfamily (ABC-C7)
evolution
the enzyme is an ATP-binding cassette (ABC) adenylate kinase and anion channel in the ATP-binding cassette (ABC) transporter protein family
malfunction
-
idiopathic chronic pancreatitis in human shows a strong genetic suscepitibility due to CFTR gene mutations
malfunction
a dysfunctional CFTR protein, e.g. by loss-of-function mutation, results in cystic fibrosis, a fatal pleiotropic disease, more than 1000 known mutations of this chloride channel result in a range of disease states. Cystic fibrosis is a Mendelian autosomal recessive disease of the young, due to its lethal nature in the early years of life, and affects roughly one in 2500 newborns with a total of 70000 people worldwide, pathophysiology, overview
malfunction
cystic fibrosis, one of the most common lethal genetic diseases, is caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel. The third most common pathogenic mutation, a glycine-to-aspartate mutation at position 551 (G551D) shows a significantly decreased open probability caused by failure of the mutant channel to respond to ATP. The CFTR-targeted drug, VX-770 (Ivacaftor), which potentiates G551D-CFTR function in vitro by boosting its Po, is approved by the american food and drug administration to treat cystic fibrosis patients carrying this mutation
malfunction
dysfunctional enzyme causes the common lethal genetic disease cystic fibrosis
malfunction
human bronchial airway epithelia derived from cystic fibrosis donors are homozygous for the F508del mutation in the enzyme
malfunction
inhibition or knockdown of CFTR inhibits ATP release from mouse epididymal principal cells. Inhibition of CFTR reduces ATP release into the lumen of cauda epididymis in mice in vivo. Defective ATP signalling in the epididymis might contribute to dysfunction of the male reproductive tract associated with CFTR mutations. Given that mutations in CFTR are a leading cause of male infertility, defective ATP signalling in the epididymis might contribute to dysfunction of the male reproductive tract associated with these mutations
malfunction
malfunction of the cystic fibrosis transmembrane conductance regulator, a gated pathway for chloride movement, causes the common life-shortening genetic disease cystic fibrosis, development of a sheep model of cystic fibrosis. The most common mutation involved in cystic fibrosis, F508del, has reduced impact on sheep CFTR function
malfunction
the cystic fibrosis transmembrane conductance regulator (CFTR) malfunction leads to the genetic disease cystic fibrosis
malfunction
-
enzyme mutations are the cause of cystsic fibrosis
malfunction
-
inhibition or knockdown of CFTR inhibits ATP release from mouse epididymal principal cells. Inhibition of CFTR reduces ATP release into the lumen of cauda epididymis in mice in vivo. Defective ATP signalling in the epididymis might contribute to dysfunction of the male reproductive tract associated with CFTR mutations. Given that mutations in CFTR are a leading cause of male infertility, defective ATP signalling in the epididymis might contribute to dysfunction of the male reproductive tract associated with these mutations
-
physiological function
expressed possum CFTR functions as a Cl- channel activated by cAMP-dependent phosphorylation
physiological function
-
depression of the intracellular pH of skeletal muscle cells stimulates ATP efflux, and CFTR plays an important role in the release mechanism
physiological function
CFTR is a functional chloride channel facilitating transmembrane anion flow down electrochemical gradients
physiological function
involvement of the enzyme in the regulation of ATP release from epithelial principal cells in the cauda epididymidis, ATP secretion into the lumen of the cauda epididymal tubule. Extracellular ATP is a key modulator of epididymal function, regulating both transepithelial transport
physiological function
ovine enzyme is a Cl- channel with enhanced conductance and ATP-dependent gating. The enzyme forms a weakly inwardly rectifying Cl- channel regulated by PKA-dependent phosphorylation, inhibited by the open-channel blocker glibenclamide. The enzyme plays a pivotal role in transepithelial ion transport
physiological function
the cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a chloride channel, which is gated by ATP when phosphorylated
physiological function
the enzyme acts as a chloride ion channel, CFTR channel pore opening is accomplished by R domain phosphorylation and the binding of ATP at the nucleotide-binding domains, where the two membrane-spanning domains are driven to change conformation to allow anions to flow, mode of action, overview
physiological function
the enzyme controls Cl- permeation across epithelia as an ABC transporter controling the flow of anions through the apical membrane of epithelia. The ABC protein function as an ion channel rather than as an active transporter
physiological function
the enzyme function in airway epithelia may depend on its adenylate kinase activity. Adenylate kinase activity is important for the function of an ATP-binding cassette transporter. Both the ATPase and adenylate kinase activities of CFTR can gate the channel. When ATP is the only nucleotide present, ATPase activity gates the channel, when AMP is present as well, adenylate kinase activity can also gate the channel
physiological function
the enzyme is a ATP-gated chloride channel. The enzyme shares gating principles with conventional ligand-gated ion channels, but the allosteric network couples ATP binding at its nucleotide binding domains with conformational changes in its transmembrane helices
physiological function
the enzyme is a phosphorylation-activated but ATP-gated chloride channel involved in the chloride permeation pathway
physiological function
the enzyme is an ATP-binding cassette adenylate kinase and anion channel
physiological function
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the channel activity of the enzyme is required for epithelial regulatory volume decrease
physiological function
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the channel activity of the enzyme is required for epithelial regulatory volume decrease
physiological function
the enzyme is crucial to epithelial salt and water homeostasis
physiological function
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involvement of the enzyme in the regulation of ATP release from epithelial principal cells in the cauda epididymidis, ATP secretion into the lumen of the cauda epididymal tubule. Extracellular ATP is a key modulator of epididymal function, regulating both transepithelial transport
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additional information
CFTR homology model indicating two salt bridges, using the homology model from the Riordan group. Residues Arg347, Asp924, and Asp993 form a triangular salt bridge early in channel openings, whereas Arg352 and Asp993 interact late in channel opening
additional information
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CFTR homology model indicating two salt bridges, using the homology model from the Riordan group. Residues Arg347, Asp924, and Asp993 form a triangular salt bridge early in channel openings, whereas Arg352 and Asp993 interact late in channel opening
additional information
enzyme residues A299, R303, N306, S307, F310, and F311 are accessible to intracellular 2-sulfonatoethyl methanethiosulfonate in both the open and closed states. The segment of transmembrane segment 5 between F311 and L323 is concealed from the pore by other TMs and/or lipid bilayers, the cytoplasmic portion of TM5 lines the pore
additional information
enzyme structure homology modelling using the crystal structure of four homologous transporters, modelling of open and closed conformations of the enzyme, structural analysis of the transmembrane cavity, detailed overview. Transitions between open and closed states of enzyme CFTR are regulated by ATP binding and hydrolysis on the cytosolic nucleotide binding domains, which are coupled with the transmembrane domains forming the pathway for anion permeation. An important role is played by residue Phe337 as a filter/gating residue
additional information
enzyme structure-function analysis, detailed overview. The unique R domain is essential to the regulation of the channel and needs to be phosphorylated by PKA to facilitate the gating cycle, domain structure
additional information
highly conserved residue Gln1291 of an ABC transporter plays an important role in adenylate kinase-dependent CFTR gating. Photolabeling of CFTR with 8-N3-[32P]AMP or 8-N3-[32P]ATP, with a photoactivatable azido (N3)-group attached to the adenine ring
additional information
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highly conserved residue Gln1291 of an ABC transporter plays an important role in adenylate kinase-dependent CFTR gating. Photolabeling of CFTR with 8-N3-[32P]AMP or 8-N3-[32P]ATP, with a photoactivatable azido (N3)-group attached to the adenine ring
additional information
molecular dynamics simulations of the enzyme in closed and open conformation, overview
additional information
photolabeling of CFTR with 8-N3-[32P]AMP or 8-N3-[32P]ATP, with a photoactivatable azido (N3)-group attached to the adenine ring, the photolabeling is enhanced by AMP and inhibited by P1,P4-di(adenosine-5') tetraphosphate and P1,P5-di(adenosine-5') pentaphosphate, which do not interact with all CFTR ATP-binding sites. Specific labeling of an AMP-binding site in the presence of ATP. Construction of a putative molecular three-dimensional model of the nucleotide-binding domain 1-nucleotide-binding domain 2 heterodimer, the crystal structure of NBD1 in complex with ATP (PDB code 1R0X) is used as template for constructing a homology model of NBD2
additional information
the enzyme is a short narrow tunnel flanked by wider inner and outer vestibules, analysis of the enzyme's pore architecture, overview. Enzyme CFTR bears a gate that is situated between amino acid residues 337 and 344 along transmembrane segment 6, encompassing the very segment that may also serve as the selectivity filter for the enzyme. The gate does not reside in the internal vestibule but is located external to position 344 in the middle of the enzyme's pore
additional information
the phosphorylated R domain, once released from ICL3, may function as a length- and gating-regulatory cross-linker between two transmembrane domains to promote the stimulatory interactions between the R domain and the ICL1/ICL4 interface
additional information
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the phosphorylated R domain, once released from ICL3, may function as a length- and gating-regulatory cross-linker between two transmembrane domains to promote the stimulatory interactions between the R domain and the ICL1/ICL4 interface
additional information
the sheep enzyme is noticeably more active than human enzyme, while the most common mutation involved in cystic fibrosis, F508del, has reduced impact on sheep CFTR function, single-channel behaviour analysis, phenotype comparison, ATP gates ovine CFTR with greater affinity and efficacy than human CFTR. Three-dimensional enzyme modeling, overview
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monomer
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1 * 170000, CFTR exitsts as monomers and multimers, the monomer is the minimum functional unit required for channel and ATPase activity, SDS-PAGE
multimer
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CFTR exitsts as monomers and multimers
?
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x * 150000, SDS-PAGE
?
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x * 150000-170000, fully glycosylated DELTAF508-CFTR, SDS-PAGE
?
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x * 140000-150000, recombinant mutant DELTAPhe508, SDS-PAGE
?
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x * 180000, untagged CFTR, SDS-PAGE, x * 210000, GFP-tagged CFTR, SDS-PAGE
?
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x * 160000, SDS-PAGE
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additional information
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enzyme of the ABC transporter family
additional information
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enzyme of the ABC transporter family
additional information
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enzyme of the ABC transporter family
additional information
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enzyme of the ABC transporter family
additional information
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sequence differences in the first membrane-spanning domains in human and Xenopus sp. are responsible for the differences in the permeation properties of human and Xenopus CFTR, the first extracellular loop influences channel gating
additional information
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the enzyme contains a tandem repeat of six transmembrane helices, each set followed by an ATP-binding domain, an additional, large, N-terminal hydrophobic region contains 4-6 transmembrane helices, is occasionally glycosylated on the cell surface and may play a key role in interactions with anionic compounds
additional information
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CFTR is composed of five domains: two membrane-spanning domains which form the channel pore, two nucleotide-binding domains and a regulatory R domain. Phosphorylation of the R domain determines channel activity, ATP hydrolysis by the nucleotide-binding domains controls gating
additional information
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enzyme function does not require a multimeric complex for function, reconstituted monomers are sufficient to mediate regulated chloride conduction and ATPase activity
additional information
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the MW of the fusion protein of glutathione S-transferase and nucleotide binding domain 1 determined by SDS-PAGE is 70000 Da
additional information
nucleotide-binding domains 1 and 2 interact in head-to-tail configuration. Protein phosphorylation by protein kinase A promotes formation of the nucleotide-binding domain heterodimer
additional information
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nucleotide-binding domains 1 and 2 of the enzyme form a complex in vivo
additional information
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structure modelling, overview
additional information
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the isolated nucleotide-binding domains exhibit adenylate kinase activity, while the full-length purified and reconstituted protein functions as a ATPase
additional information
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CFTR is a polytopic membrane protein that functions as a Cl- channel and consists of two membrane spanning domains, two cytosolic nucleotide binding domains, and a cytosolic regulatory domain. The assembly of CFTR into an ion channel is complicated because it requires the coordinated folding and assembly of its membrane and cytoplasmic domains into a functional unit. Misfolding of CFTR and analysis by trypsin proteolysis patterns of misfolded CFTR, model of calnexin action in CFTR folding, overview
additional information
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comparison of CFTR protein sequences to those of other ABC transporters, structure analysis, overview. A residue, identified as being involved in CFTR functional divergence, by virtue of being both CFTR-specific and conserved among all CFTR orthologs, is R352 in the sixth transmembrane helix, TM6. R352 interacts with absolutely conserved D993 in TM9 to stabilize the open-channel state
additional information
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reconstruction of the three-dimensional structure from negatively stained EM images of purified glycosylated mature CFTR, CFTR comprises a small dome-shaped extracellular and membrane-spanning domain and a large cytoplasmic domain with orifices beneath the putative transmembrane domain
additional information
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the four domains comprising CFTR are encoded by a single gene comprising an N-terminal TMD1 and NBD1 and a C-terminal TMD2 and NBD2. In the head subdomain, conserved motifs include the Walker A and B motifs involved in nucleotide coordination and hydrolysis, while the conserved ABC signature sequence, LSGGQXXR, is in the tail subdomain
additional information
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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. Aromatic clusters mediate domain-swapping interactions, structure modelling, overview
additional information
the nucleotide binding sites form a head-to-tail dimer with two ATP-binding sites located at the dimer interface, homology modeling of the nucleotide binding domain 2 based on the crystal structure, PDB code 1XMI, construction of a NBD1-NBD2 heterodimer by protein-protein docking, overview
additional information
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the nucleotide binding sites form a head-to-tail dimer with two ATP-binding sites located at the dimer interface, homology modeling of the nucleotide binding domain 2 based on the crystal structure, PDB code 1XMI, construction of a NBD1-NBD2 heterodimer by protein-protein docking, overview
additional information
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polyethylene glycols with a hydrodynamic radius smaller than 0.95 nm added from the intracellular side greatly suppress the inward unitary anionic conductance, whereas only molecules with hydrodynamic radius below 0.62 nm applied extracellularly are able to affect the outward unitary anionic currents. Larger molecules with hydrodynamic radius of 1.16-1.84 nm added from either side are completely excluded from the pore and have no significant effect on the single-channel conductance. The cut-off radius of the inner entrance of CFTR channel pore is 1.19 nm. The outer entrance is narrower with its cut-off radius of 0.70 nm and is dilated to about 0.93 nm when a non-hydrolyzable ATP analog, 5'-adenylylimidodiphosphate, is added to the intracellular solution
additional information
construction of a putative molecular three-dimensional model of the nucleotide-binding domain 1-nucleotide-binding domain 2 heterodimer
additional information
enzyme domain structure consisting of two transmembrane domains, two nucleotide?binding domains, and one regulatory domain, overview. Head-to-tail arrangement of the nucleotide-binding domain dimer
additional information
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sequence differences in the first membrane-spanning domains in human and Xenopus sp. are responsible for the differences in the permeation properties of human and Xenopus CFTR, the first extracellular loop influences channel gating
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A196C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
A252C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
A299C
site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
A326C
site-directed mutagenesis, the substituted cysteine does not respond to neither internal nor external 2-sulfonatoethyl methanethiosulfonate and is inaccessible to channel-permeant thiol-specific reagent [Au(CN)2]-
A367C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
A462F
site-directed mutagenesis, the mutation abolishes nucleotide interaction with ATP-binding site 1, the mutant exhibits a low, ATP-dependent open probability due to a reduced opening rate with a normal burst duration. The A462F mutation interfers with processing and trafficking to the cell membrane
D1152H
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mutation in the CFTR gene causing cystic fibrosis
D1370N
site-directed mutagenesis of a conserved residue in the Walker B motif of ATP-binding site 2, the mutation abolishes P1,P5-di(adenosine-5') pentaphosphate, Ap5A, inhibition of current
D924R
site-directed mutagenesis, the mutant shows brief transitions to all conductance levels, it can reach the open state but not stably
D993R
site-directed mutagenesis, the mutant opens to all 3 levels, but none are stable. The mutant can reach the open state but not stably
DELTAF508/F409L/F4929S/F433L/G550E/R553Q/R555K/H667R
mutant bearing an in-frame deletion without a phenylalanine residue at position 508 within nucleotide-binding domain 1 as well as several solubilizing mutations: Crystal structure refined at 2.55 A: The side chain of residue V510 in this loop is completely solvent exposed
DELTAF508/F429S/F494N/Q637R
mutant bearing an in-frame deletion without a phenylalanine residue at position 508 within nucleotide-binding domain 1 as well as several solubilizing mutations: Crystal structure refined at 2.3 A: The side chain of residue V510 in this loop is completely solvent exposed
DELTAF508/F494N/Q637R
mutant bearing an in-frame deletion without a phenylalanine residue at position 508 within nucleotide-binding domain 1 as well as several solubilizing mutations: Crystal structure refined at 2.05 A: The side chain of residue V510 in this loop is completely solvent exposed
E543C/T996C
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cross-linking between residues T996C and E543C at the CL3/NBD1 interface rapidly and reversibly arrests channel gating
F310C
site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
F311C
site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
F337A
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the mutation exhibits strong gain of function effects
F337L
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the mutation exhibits strong gain of function effects
F337S
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the mutation exhibits strong gain of function effects and markedly increases the activities of enzyme constructs that cannot be activated by ATP
F409L/F4929S/F433L/G550E/R553Q/R555K/H667R
mutant bearing no in-frame deletion of a phenylalanine residue at position 508 but with several solubilizing mutations: Crystal structure refined at 2.55 A: The side chain of residue V510 in this loop is buried
F508C/E1371S
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mutation in CFTR mutant lacking all cysteine residues due to replacement by alanine, except Cys590 and Cys592, which are replaced by leucine. Mutation F508C prevents the cysless E1371S channel from maintaining the permanently open state, allowing closing to occur. Specifically, benzyl-methanethiosulphonate modification restores the gating behaviour to that of cysless E1371S
G134D/F337C
site-directed mutagenesis, increased accessibility of the side chain of 338C in the closed state compared to mutant F337C
G134D/T338C
site-directed mutagenesis, limited accessibility of the side chain of 338C in the closed state compared to mutant T338C
G194C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
G241C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
G551A
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the signature sequence mutant does not show activation of the the CFTR chloride channel activity by Cd2+ in contrast to mutant G551D
G551C
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the signature sequence mutant shows activation of the the CFTR chloride channel activity by Cd2+ in contrast to the wild-type enzyme
G551D/W401F
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mutation based on G551D in NBD1 signature motif, which completely abolishes ATP-induced openings of the channel. Additional mutation W401Y become ATP-responsive and are potentiated by N6-2-phenylethyl-ATP
G551D/W401Y
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mutation based on G551D in NBD1 signature motif, which completely abolishes ATP-induced openings of the channel. Additional mutation W401Y become ATP-responsive and are potentiated by N6-2-phenylethyl-ATP
G551D/Y1219F
increased ATP washout compared to mutant G551D
G551D/Y1219I
increased ATP washout compared to mutant G551D
G551E
site-directed mutagenesis, the mutant exhibits a similar phenotype like mutant G551D
G551K
site-directed mutagenesis, the mutant does not exhibit a similar phenotype like mutant G551D
G551S
site-directed mutagenesis, the mutant does not exhibit a similar phenotype like mutant G551D
I331C
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modification rate by methanethiosulfonate ethyl ammonium and (2-sulfonatoethyl) methanethiosulfonate is slower in the open state than in the closed state
K335E
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conversion from a low I- permeability pore to a high I- permeability pore
K464H
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mutant of the NBF1+R segment (nucleotide binding domain 1 and regulatory domain), Vmax is reduced about 50%
K95D
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conversion from a low I- permeability pore to a high I- permeability pore
L172C/D1341C
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the cross-linking between L172C of CL1 and D1341C of NBD2 rapidly and reversibly inhibited channel gating
L188C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
L197C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
L323C
site-directed mutagenesis, the substituted cysteine does not respond to neither internal nor external 2-sulfonatoethyl methanethiosulfonate and is inaccessible to channel-permeant thiol-specific reagent [Au(CN)2]-
L333C
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modification rate by methanethiosulfonate ethyl ammonium and (2-sulfonatoethyl) methanethiosulfonate is slower in the open state than in the closed state
L548C
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the signature sequence mutant shows activation of the the CFTR chloride channel activity by Cd2+ in contrast to the wild-type enzyme
M244C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
M245C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
N186C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
N189C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
P355A
gain of function mutation of a conserved proline at the base of the pore-lining transmembrane segment 6. Multiple substitutions of this proline promote ATP-free CFTR activity and activation by the weak agonist, 5'-adenylyl-beta/gamma-imidodiphosphate (AMP-PNP)
P355F
gain of function mutation of a conserved proline at the base of the pore-lining transmembrane segment 6. Multiple substitutions of this proline promote ATP-free CFTR activity and activation by the weak agonist, 5'-adenylyl-beta/gamma-imidodiphosphate (AMP-PNP)
P355S
gain of function mutation of a conserved proline at the base of the pore-lining transmembrane segment 6. Multiple substitutions of this proline promote ATP-free CFTR activity and activation by the weak agonist, 5'-adenylyl-beta/gamma-imidodiphosphate (AMP-PNP)
Q1291A
mutating Gln1291 disrupts adenylate kinase- but not ATPase-dependent gating, and reduces channel activity in airway epithelia. The mutant displays significantly reduced Cl- channel function in well differentiated primary human airway epithelia. Gln1291 mutations interfere with Ap5A inhibition of CFTR current
Q1291F
mutating Gln1291 disrupts adenylate kinase- but not ATPase-dependent gating, and reduces channel activity in airway epithelia. The mutant displays significantly reduced Cl- channel function in well differentiated primary human airway epithelia. Gln1291 mutations interfere with Ap5A inhibition of CFTR current. The Q1291F mutation disrupts photolabeling of the AMP-binding site with 8-N3-AMP
Q1291G
mutating Gln1291 disrupts adenylate kinase- but not ATPase-dependent gating, and reduces channel activity in airway epithelia. The mutant displays significantly reduced Cl- channel function in well differentiated primary human airway epithelia. Gln1291 mutations interfere with Ap5A inhibition of CFTR current
Q1291H
mutating Gln1291 disrupts adenylate kinase- but not ATPase-dependent gating, and reduces channel activity in airway epithelia. The mutant displays significantly reduced Cl- channel function in well differentiated primary human airway epithelia. Gln1291 mutations interfere with Ap5A inhibition of CFTR current
Q1291W
mutating Gln1291 disrupts adenylate kinase- but not ATPase-dependent gating, and reduces channel activity in airway epithelia. The mutant displays significantly reduced Cl- channel function in well differentiated primary human airway epithelia. Gln1291 mutations interfere with Ap5A inhibition of CFTR current
Q1291Y
mutating Gln1291 disrupts adenylate kinase- but not ATPase-dependent gating, and reduces channel activity in airway epithelia. The mutant displays significantly reduced Cl- channel function in well differentiated primary human airway epithelia. Gln1291 mutations interfere with Ap5A inhibition of CFTR current
Q552C
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the mutant does not show activation of the the CFTR chloride channel activity by Cd2+
R303C
site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
R334C/E1126A
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this double mutant is insensitive to 0.05 mM ZnCl2
R334W
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amount of Cl- currents is less than 30% that of the wild-type CFTR
R347A
site-directed mutagenesis, the mutant emphasizes s1 state, brief transitions to s2 state and the open state, it can reach the open state but not stably
R347A/R352A
site-directed mutagenesis, the mutant opens to all 3 levels, s1 state is much more stable than in the wild-type, s2 state is unstable, the open state is unstable. The mutant can reach the open state but not stably
R347D/D924R
site-directed mutagenesis, the mutant emphasizes s2 state, rare and brief transitions to the open state, it can reach the open state but not stably
R347D/D924R/D993R
site-directed mutagenesis, the mutant opens to all 3 levels, s1 state is much more stable than in the wild-type, s2 state is relatively stabilized, the open state is unstable. The mutant can reach the open state but not stably
R347D/D924R/R352E/D993R
site-directed mutagenesis, the mutant primarily flickers between s2 state and the open state, s1 state is much more stable than in the wild-type, the mutant shows slightly reduced single channel conductance, it can reach the open state but not stably
R347D/D993R
site-directed mutagenesis, the mutant shows very stable s2 state, but rare and brief transitions to both s1 state and the open state. It can reach the open state but not stably
R347K
site-directed mutagenesis, the mutant is wild-type-like
R347P
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amount of Cl- currents is less than 30% that of the wild-type CFTR
R352E/D924R
site-directed mutagenesis, the mutant opens to all 3 levels, but none are stable. The mutant can reach the open state but not stably
R352E/E1104R
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channels bearing the R352E mutation, or the double mutant R352E/E1104R, exhibit frequent transitions to subconductance levels
R352X
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charge-destroying mutations at R352 alter CFTR single channel behavior
R553C
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the mutant does not show activation of the the CFTR chloride channel activity by Cd2+
S1248F
site-directed mutagenesis, the mutation abolishes nucleotide interaction with ATP-binding site 2, the mutant exhibits a low, ATP-dependent open probability due to a reduced opening rate with a normal burst duration. The S1248F mutation does not interfere with processing and trafficking to the cell membrane
S341C
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the cysteine introduced at a position in the pore-lining TM6 region of CFTR is accessible to extracellular methanesulfonate reagents, charge-dependent changes in I-V shape in this mutant, indicating that deposition of charge at this position also alters anion movement in the pore
S549C
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the signature sequence mutant shows activation of the the CFTR chloride channel activity by Cd2+ in contrast to the wild-type enzyme
S573E
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mutation in nucleotide-binding domain 1, retains wild-type nucleotide binding affinity, does not confer additional ATPase activity to a heterodimer with nucleotide-binding domain 2 fragment mutant E1371Q
S768A
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has higher activity than wild type channels, confirming the inhibitory influence of Ser 768
T1122C
-
0.05 mM ZnCl2 decreases the channel conductance of the mutant by about 55.2%. Internal curcumin reverses the Zn2+ inhibition
T122H
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the mutant exhibits Cl--independent Zn2+ inhibition
T547C
-
the mutant does not show activation of the the CFTR chloride channel activity by Cd2+
V171C/L408C
-
the mutation has essentially no influence on gating
W1282X
-
mutation in the CFTR gene causing cystic fibrosis
W356C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
W401F
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mutation W401Y facilitates channel closure from the lock-open state. W401F appears better than W401Y, which is in turn superior to tryptophan, in stabilizing the lock-open state
W401G
little effect on the sensitivity of the channel opening rate to the concentration of ATP, but shortens the open time constant
W401Y
-
mutation W401Y facilitates channel closure from the lock-open state. W401F appears better than W401Y, which is in turn superior to tryptophan, in stabilizing the lock-open state
Y1219F
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mutation at NBD2, decreases ATP binding affinity and significantly increases the prevalence of the long-lasting opening events with a time constant of tens of seconds
Y1219I
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mutation at NBD2, decreases ATP binding affinity and significantly increases the prevalence of the long-lasting opening events with a time constant of tens of seconds
Y1219W
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mutation at NBD2, decreases ATP binding affinity and significantly increases the prevalence of the long-lasting opening events with a time constant of tens of seconds
E1372Q
the mutation abolishes ATP hydrolysis and slows the pore-closing rate by about 1000fold as compared to the wild type enzyme
E1372Q
-
the mutation abolishes the ATPase activity of the enzyme
D572N
site-directed mutagenesis of a conserved residue in the Walker B motif of ATP-binding site 1, the mutation does not abolish P1,P5-di(adenosine-5') pentaphosphate, Ap5A, inhibition of current
D572N
-
the mutation disrupts the interaction of ATP with ATP-binding site 1
DELTAF508
in-frame deletion without a phenylalanine residue at position 508 within nucleotide binding domain 1: mass spectral measurements of backbone amide 1H/2H exchange rates in reveal that mutant DELTAF508 increases backbone dynamics at residues 509-511 and the adjacent protein segments but not elsewhere in NBD1. These measurements also confirm a high level of flexibility in the protein segments exhibiting variable conformations in the crystal structures
DELTAF508
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the deletion mutation is associated with cystic fibrosis
E1371Q
-
low level of residual ATPase activity, no adenylate kinase activity
E1371Q
-
mutation in nucleotide-binding domain 2, prevents ATP hydrolysis without affecting ATP binding and stabilizes the open state of the channel by almost 1000fold
E1371Q
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mutation in nucleotide-binding domain 2, retains wild-type nucleotide binding affinity, but ATPase activity is abolished in a heterodimer with nucleotide-binding domain 1 fragment
E1371S
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mutation in CFTR mutant lacking all cysteine residues due to replacement by alanine, except Cys590 and Cys592, which are replaced by leucine. Mutant can be locked in an open state
E1371S
-
the mutant has no ATPase activity
F337C
site-directed mutagenesis
F337C
-
the cysteine introduced at a position in the pore-lining TM6 region of CFTR is accessible to extracellular methanesulfonate reagents, the mutant becomes significantly more inwardly rectified in the presence of sodium (2-sulfonatoethyl)methanesulfonate
F337C
-
the mutation exhibits strong gain of function effects
F508del
the in-frame deletion causes cystic fibrosis
F508del
-
the mutation is associated with cystic fibrosis
G1349D
site-directed mutagenesis, a mutation associated with the genetic disease cystic fibrosis
G1349D
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the mutation is associated with cystic fibrosis and greatly disturbs enzyme intraburst gating
G551D
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mutation in ABC signature motif, markedly reduced ATPase activity, no adenylate kinase activity
G551D
mutation in ATP-binding pocket 2, abolishes ATP-dependent gating, results in an open probability of the channel that is 100fold lower than that of wild-type. The ATP analog N6-(2-phenylethyl)-ATP increases G551D currents mainly by increasing the open time of the channel. This effect is reduced when N6-(2-phenylethyl)-ATP is applied together with ATP
G551D
-
the signature sequence mutation completely abrogates the ATP-dependent gating of the CFTR chloride channel and results in a severe phenotype of cystic fibrosis. The mutant shows highly sensitivity to activation by Cd2+ in contrast to the wild-type enzyme
G551D
third most common pathogenic naturally occuring mutation of the enzyme, mutant G551D shows a significantly decreased open probability caused by failure of the mutant channel to respond to ATP. The CFTR-targeted drug, VX-770 (Ivacaftor) potentiates G551D-CFTR function in vitro by boosting its open probability, in the presence of VX-770, G551D-CFTR becomes responsive to ATP, albeit with an unusual time course. A sudden removal of ATP in excised inside-out patches containing the mutant enzyme elicits an initial increase in macroscopic G551D-CFTR current followed by a slow decrease, in contrast to wild-type channels. The stimulatory effect of ATP is abolished by the G551D mutation despite a normal surface expression of the mutant proteins. The two ATP-binding sites in the G551D mutant mediate opposite effects on channel gating. Introduction of mutations that specifically alter ATP-binding affinity in either nucleotide-binding domain (NBD1 or NBD2) into the G551D background, the disease-associated mutation converts site 2, formed by the head subdomain of NBD2 and the tail subdomain of NBD1, into an inhibitory site, whereas site 1 remains stimulatory
G551D
-
the mutation impairs ATP hydrolysis and thereby makes the enzyme refractory to cAMP stimulation
G551D/Y1219G
lowered binding affinity at the ATP binding-pocket 2, no influence on the increasing of the open time of the channel by N6-(2-phenylethyl)-ATP
G551D/Y1219G
increased ATP washout compared to mutant G551D
K1250A
-
modulation of the on-rate of venom binding for intraburst block
K1250A
site-directed mutagenesis of a conserved residue in the Walker A motif of ATP-binding site 2, the mutation abolishes P1,P5-di(adenosine-5') pentaphosphate, Ap5A, inhibition of current
K335C
-
modification rate by methanethiosulfonate ethyl ammonium and (2-sulfonatoethyl) methanethiosulfonate is slower in the open state than in the closed state
K335C
-
the cysteine introduced at a position in the pore-lining TM6 region of CFTR is accessible to extracellular methanesulfonate reagents
K464A
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mutant of the NBF1+R segment (nucleotide binding domain 1 and regulatory domain), Vmax is reduced about 50%
K464A
site-directed mutagenesis of a conserved residue in the Walker A motif of ATP-binding site 1, the mutation does not abolish P1,P5-di(adenosine-5') pentaphosphate, Ap5A, inhibition of current
K464A
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the mutation disrupts the interaction of ATP with ATP-binding site 1
N306C
site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
N306C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
R334C
site-directed mutagenesis
R334C
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modification rate by methanethiosulfonate ethyl ammonium and (2-sulfonatoethyl) methanethiosulfonate is not dependent on open/closed state
R334C
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the cysteine introduced at a position in the pore-lining TM6 region of CFTR is accessible to extracellular methanesulfonate reagents
R334C
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the mutant enzyme is unaffected by external ZnCl2 even at 5 mM concentrations. At steady activation, 0.05 mM external ZnCl2 inhibits its channel conductance by 54.47%. Internal curcumin reverses the Zn2+ inhibition
R347D
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inhibition by 10 mM glutathione is higher than that of the wild-type enzyme. The Km-value for ATP in presence of protein kinase A is 3fold lower than that of the wild-type enzyme. The Km-value for ATP in absence of protein kinase A is 1.1fold higher than that of the wild-type enzyme
R347D
site-directed mutagenesis, the mutant emphasizes s1 state, no transitions to s2 state and the open state, the mutant cannot reach the open state
R352E
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channels bearing the R352E mutation exhibit frequent transitions to subconductance levels
R352E
site-directed mutagenesis, the mutant opens to all 3 levels, s1 state is much more stable than in wild-type, s2 state is unstable, the open state is unstable. The mutant can reach the open state but not stably
R352E/D993R
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channels bearing the revertant mutation R352E/D993R, primarily exhibit transitions to the full conductance level
R352E/D993R
site-directed mutagenesis, the mutant is wild type-like, with increased transitions to s1 and s2 states, it shows slightly reduced single-channel conductance, the impact on the open state is wild type-like
S307C
site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
S307C
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[2-sulfonatoethyl] methanethiosulfonate-sensitive cysteine mutant
T338C
site-directed mutagenesis
T338C
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modification rate by methanethiosulfonate ethyl ammonium and (2-sulfonatoethyl) methanethiosulfonate is slower in the open state than in the closed state
T338C
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Au(CN)2 - can modify T338C-CFTR with or without cAMP stimulation in contrast to the wild-type enzyme
T338C
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the cysteine introduced at a position in the pore-lining TM6 region of CFTR is accessible to extracellular methanesulfonate reagents
W401G/G551D
significant reduction of the increasing of the open time of the channel by N6-(2-phenylethyl)-ATP
W401G/G551D
acceleration of the slow-phase current decay by the W401G mutation
Y1219G
decrease in the apparent affinity for ATP by 50fold
Y1219G
decreases the apparent affinity of ATP and P-ATP
Y1219G
-
mutation at NBD2, decreases ATP binding affinity and significantly increases the prevalence of the long-lasting opening events with a time constant of tens of seconds
G551D
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the mutation impairs ATP hydrolysis and thereby makes the enzyme refractory to cAMP stimulation
G551D
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channel does not open in response to phosphorylation by protein kinase
additional information
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the most common mutation in cystic fibrosis, DELTAF508-CFTR, leads to a trafficking-impaired protein that gets degraded in the cell. G551D is a trafficking-competent but misfunctional protein
additional information
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the mutant enzyme CFTRG551D, associated with human disease, exhibits defective ATPase activity
additional information
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deletion of the insertion, but not the extension, of nucleotide-binding domain 1 speeds closing from locked-open bursts, omission of the nucleotide-binding domain 1 insertion or extension causes no major perturbation of the pore architecture
additional information
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construction of 26 Cys-substituted mutant and analysis of change in cAMP-activated whole cell conductance
additional information
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construction of human-murine CFTR chimeras with sequences from nucleotide-binding domain 1, nucleotide-binding domain 2, or the regulatory domain of human CFTR replaced by the equivalent regions of murine CFTR. The gating behavior of human-murine regulatory domain and human CFTR are indistinguishable, whereas human-murine nucleotide-binding domain 1 and human-murine nucleotide-binding domain2 have subtle effects on channel gating, prolonging both burst duration and interburst interval. By contrast, human-murine nucleotide-binding domain1-2, containing both nucleotide-binding domains of murine CFTR, reproduces the gating behavior of the subconductance state of murine CFTR, which has dramatically prolonged channel openings
additional information
mutation C590V/592V plus mutation of the remaining 16 Cys residues to Ser, or mutation C590L/592L plus mutation of the remaining 16 Cys residues to Ser results in a mutant protein with about 30% of wild-type activity. This Cys-free mutant allows for the sequential introduction of target Cys residues for cross-linking studies. Introduction of S1248C, S549C, S605C, A1374C, A462C, S1347C into the Cys-free mutant and analysis of crosslinks demonstrates that nucleotide-binding domains 1 and 2 interact in a head-to-tail configuration. Protein phosphorylation by protein kinase A promotes formation of the nucleotide-binding domain heterodimer
additional information
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construction of Cys-less mutant CFTR. The most common naturally occurring mutation, deletion of phenylalanine 508, and many other disease-associated mutations occur in the nucleotide binding domains and the cytoplasmic loops of the membrane-spanning domains
additional information
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construction of isogenic lung epithelial cell lines expressing either mutant or wild-type CFTR, development of a series of nominally isogenic, clonal bronchial epithelial cell lines stably expressing a 3 GFP-N-terminal labeled WT-CFTR, using as a parental cell line the IB3-1 cells initially obtained 4 from a cystic fibrosis patient with DELTAF508/W1282X cftr alleles, Pseudomonas aeruginosa infection phenotypes, overview
additional information
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construction of truncation mutant DELTANBD2 CFTR terminating at residue 1172
additional information
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deletion of Phe508 constitutes the most prevalent of a number of mutations in CFTR that cause cystic fibrosis, mutation leads to CFTR misfolding and retention in the endoplasmic reticulum, as well as impaired channel activity. The biosynthetic defect can be partially overcome by small molecule correctors, once at the cell surface, small-molecule potentiators enhance the channel activity of DELTAPhe508 CFTR, VRT-532 exhibit both corrector and potentiator functions
additional information
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enzyme knockout by RNAi, folding defects caused by deletion of F508 that occur before and after the calnexin-dependent association of membrane spanning domains MSD1 and MSD2, mechanism, overview
additional information
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introduction of an extracellular 3HA-tag, consisting of amino acid residues of SLEYPYDVPDYASYPYDVPDYAYPYDVPD, into the 4th extracellular loop after residue 897 in the G551D CFTR mutant and the wild-type enzyme as well as into the mutant DELTAF508 CFTR. Heterologous overexpression fails to alter endocytic organellar pH
additional information
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mutations in the CFTR gene cause cystic fibrosis, phenotypes in the Jewish and Arab population in Israel, overview
additional information
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the most common naturally occurring mutation, DELTAF508, omits the phenylalanine residue at position 508 in the first nucleotide binding domain, NBD1, of CFTR. The mutant protein is retained in the endoplasmic reticulum and degraded by the ubiquitin-proteasome system. Expression of NBD1 plus the regulatory domain of DELTAF508 CFTR, i.e. DELTAFRD, restores the biogenesis of mature DELTAF508 CFTR protein. In addition, DELTAFRD elicits a cAMP-stimulated anion conductance response in primary human bronchial epithelial cells isolated from homozygous DELTAF508 cystic fibrosis patients
additional information
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CFTR gating is mainly controlled by ATP binding and hydrolysis in site 2, whereas site 1, which harbors several non-canonical substitutions in ATP-interacting motifs, is considered degenerated. The degenerated site 1 can be rebuilt to complement or support site 2 for CFTR function
additional information
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introduction of Cys residues in a CFTR variant in which all cysteines had been removed by mutagenesis, and patch clamp recording to quantify the rate of access of cysteine-reactive probes. The large [2-sulfonatoethyl]methanethiosulfonate molecule and permeant Au(CN)2- ions, are applied to either side of the membrane to modify cysteines substituted for Leu-102 in the first transmembrane region and Thr-338 in the sixth transmembrane region. Channel opening and closing are altered by mutations in the nucleotide binding domains of the channel. For both [2-sulfonatoethyl]methanethiosulfonate and Au(CN)2-, access to these two cysteines from the cytoplasmic side is faster in open channels, whereas access to these same sites from the extracellular side is faster in closed channels. These results are consistent with alternating access to the transmembrane regions, however with the open state facing inwardly and the closed state facing outwardly
additional information
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introduction of cysteine resiudes to a human CFTR variant from which all cysteines had been removed by mutagenesis and which includes a mutation in NBD1, V510A, to increase the level of protein expression in the cell membrane. Methanethiosulfonate reagents modify cysteines introduced at 14 of 16 sites studied in the juxtamembrane region of loop 3, in all cases leading to inhibition of channel function. In most cases, both the functional effects of modification and the rate of modification are similar for negatively and positively charged methanethiosulfonate reagents. Single-channel recordings indicate that, at all sites, inhibition is the result of an methanethiosulfonate reagent-induced decrease in channel open probability, in no case the conductance of open channels is altered by modification. For mutants L941C, I942C, K946C, I947C, H950C, L973C, N974C, S977C, I980C, A981C, and I982C, macroscopic currents are inhibited by both 2-sulfanoethyl methanethiosulfonate and [2-(trimethylammonium)ethyl] methanethiosulfonate. Mutant T943C, V944C, and R975C are inhibited by 2-sulfanoethyl methanethiosulfonate but not significantly affected by [2-(trimethylammonium)ethyl] methanethiosulfonate exposure. Mutants F976C and L983C, are not significantly affected by either 2-sulfanoethyl methanethiosulfonate or [2-(trimethylammonium)ethyl]methanethiosulfonate
additional information
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introduction of cysteine resiudues to a Cys-less mutant and cysteine scanning of TM12 of CFTR using intracellularly applied 2-sulfonatoethyl methanethiosulfonate reagents. Data show high reaction rates of substituted cysteines toward the probes, strong blocker protection of cysteines against reaction, and reaction-induced alterations in channel conductance, supporting the idea that TM12 of CFTR contributes to the lining of the ion permeation pathway
additional information
each class of gain-of-function mutation in the transmembrane segements functionally rescues ATP binding mutants the enzyme presumably by enhancing ATP occupancy of the nucleotide-binding domains (i.e. by allosteric rescue of ATP binding defects in the nucleotide-binding domains), overview
additional information
human bronchial airway epithelia derived from cystic fibrosis donors are homozygous for the F508del mutation in the enzyme. Photolabeling of CFTR with 8-N3-[32P]AMP or 8-N3-[32P]ATP. Cell surface biotinylation of wild-type and mutant enzyme CFTR
additional information
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human bronchial airway epithelia derived from cystic fibrosis donors are homozygous for the F508del mutation in the enzyme. Photolabeling of CFTR with 8-N3-[32P]AMP or 8-N3-[32P]ATP. Cell surface biotinylation of wild-type and mutant enzyme CFTR
additional information
influence of Gln1291 mutations on single-channel gating, overview
additional information
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influence of Gln1291 mutations on single-channel gating, overview
additional information
open or closed state dependent alterations of the accessibility of the mutated residues for [Au(CN)2]- in presence or absence of ATP, overview. Preferential reactivity of 334C, 335C, and 337C to external [Au(CN)2]- in closed channels
additional information
photolabeling of CFTR with 8-N3-[32P]AMP or 8-N3-[32P]ATP
additional information
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CFTR knockout mice B6, aortas significantly more constricted than control arteries, less sensitive to the relaxing action of VIP, and fail to relax in the presence of CFTR activators
additional information
-
construction of human-murine CFTR chimeras with sequences from nucleotide-binding domain 1, nucleotide-binding domain 2, or the regulatory domain of human CFTR replaced by the equivalent regions of murine CFTR. The gating behavior of human-murine regulatory domain and human CFTR are indistinguishable, whereas human-murine nucleotide-binding domain 1 and human-murine nucleotide-binding domain 2 have subtle effects on channel gating, prolonging both burst duration and interburst interval. By contrast, human-murine nucleotide-binding domain1-2, containing both nucleotide-binding domains of murine CFTR, reproduces the gating behavior of the subconductance state of murine CFTR, which has dramatically prolonged channel openings
additional information
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CFTR complementation of cystic fibrosis respiratory epithelia has no effect on the endosomal pH
additional information
the most common mutation involved in cystic fibrosis, F508del, has reduced impact on sheep CFTR function, single-channel behaviour analysis, phenotype, overview. Phylogenetic analysis of CFTR structure and function demonstrates that subtle changes in structure have pronounced effects on channel function and the consequences of the cystic fibrosis mutation F508del
additional information
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CFTR mutants tm1Unc, no detectable ovarian hyperstimulation syndrome symptoms by ovarian hyperstimulation
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