Information on EC 3.6.3.49 - channel-conductance-controlling ATPase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.6.3.49
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RECOMMENDED NAME
GeneOntology No.
channel-conductance-controlling ATPase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + H2O = ADP + phosphate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of phosphate bond
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-
-
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transmembrane transport
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-
-
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SYSTEMATIC NAME
IUBMB Comments
ATP phosphohydrolase (channel-conductance-controlling)
ABC-type (ATP-binding cassette-type) ATPase, characterized by the presence of two similar ATP-binding domains. Does not undergo phosphorylation during the transport process. An animal enzyme that is active in forming a chloride channel, the absence of which brings about cystic fibrosis. It is also involved in the functioning of other transmembrane channels.
CAS REGISTRY NUMBER
COMMENTARY hide
9000-83-3
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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-
-
Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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SwissProt
Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
shark
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-
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
malfunction
metabolism
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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
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
AMP + H2O
ADP + phosphate
show the reaction diagram
ATP + H2O
?
show the reaction diagram
ATP + H2O
ADP + phosphate
show the reaction diagram
GTP + H2O
?
show the reaction diagram
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-
-
-
?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + H2O
ADP + phosphate
show the reaction diagram
additional information
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+
-
stimulates
Cd2+
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coordinated by residues G551, S549, and L548. Highly activating the chloride channel activity of CFTR mutant G551D in absence of ATP, but not of wild-type CFTR or mutant G551A
Co2+
-
best divalent metal activator
K+
-
activates CFTR in myocytes
Mn2+
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activates
additional information
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anions bind inside the Cl-channel pore, the pore discriminates between anions
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-(pyridin-4-yl)-4H-benzo[h]chromen-4-one
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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
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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
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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
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5-nitro-2-(3-phenylpropylamine)benzoic acid
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8-azido-ATP
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is retained at nucleotide-binding domain 1, NBD1 at low temperature even in the absence of bivalent cations
adenylyl-imidodiphosphate
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modulation of the on-rate of venom binding for intraburst block
adenylyliminodiphosphate
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Antibody
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inhibits CFTR, alleviation of ovarian hyperstimulation syndrome symptoms
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ATP-P3-[1-(2-nitrophenyl)ethyl]ester
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Au(CN)2-
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inhibits the ion channel function
bumetanide
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blocks CFTR
Cd2+
-
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CFTRinh-172
CFTRinh172
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blocks CFTR
detergent SB-300
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blocks forskolin-stimulated CFTR Cl- secretion by 92.2%
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detergent SB-303
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decreases stimulated CFTR Cl- currents by 98%
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diadenosine polyphosphate
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diphenylamine-2,2'-dicarboxylic acid
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fully inhibits
diphenylamine-2-carboxylate
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Fe3+
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binds at the interface of the regulatory (R) domain and intracellular loop (ICL) 3
forskolin
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abolishes the enzyme activity, which is reversible by DTT
genistein
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bindings of genistein and ATP are competitive
glibencalmide
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an open-channel blocker
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glibenclamide
HgCl2
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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
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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
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competitive with ATP, binds to ATP-binding pocket 1
niflumic acid
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P1,P5-di(adenosine-5') pentaphosphate
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Ap5A, an adenylate kinase inhibitor that partially inhibits wild-type CFTR, and inhibition can be attenuated by high ATP concentrations
phosphatidylinositol 4,5-bisphosphate
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applied to phosphorylated CTFR may inhibit the CTFR chloride current
progesterone
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supresses CFTR expression, alleviation of ovarian hyperstimulation syndrome symptoms
Tolbutamide
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vanadate
venom
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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
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VRT-532
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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
[Au(CN)2]-
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additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
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1,3-diallyl-8-cyclohexylxanthine
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17beta-estradiol
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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
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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
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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
5-hydroxytryptamine
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activates CFTR in myocytes
8-cyclopentyl-1,3-dipropylxanthine
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activates prephosphorylated CFTR by binding directly to CFTR
A23187
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ATP
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half-maximal activation by 0.05 mM
BeF3
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amount of Cl- currents is less than 30% that of the wild-type CFTR
benzimidazolone compounds
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-
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benzoquinolizinium compounds
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-
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calnexin
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Dependence on calnexin for proper assembly of CFTR’s 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
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curcumin
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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
DiBucAMP
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diphosphate
estrogen
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high amounts upregulate CFTR expression
flavonoid
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fluorescein derivative
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forskolin
genistein
IBMX
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isoprenaline
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induces the chloride current
isoproterenol
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stimulates
KCN
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without cAMP stimulation, KCN treatment increases CFTR Cl- conductance by 1.95fold, whereas after cAMP stimulation KCN treatment increases conductance by 13.7fold
lubiprostone
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MPB-07
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stimulates
MPB-91
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stimulates
NS-004
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activates prephosphorylated CFTR by binding directly to CFTR
phosphatidylinositol 4,5-bisphosphate
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activation of CTFR, which results in ATP responsiveness, AtP opens nonphosphorylated CTFR after application of phosphatidylinositol 4,5-bisphosphate
Vasoactive intestinal peptide
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stimulates
VO43-
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prolongs the duration of the burst of channel activity
VRT-532
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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
xanthine
-
-
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.28 - 0.45
ADP
0.03 - 0.07
AMP
0.00331 - 2.2
ATP
0.15
MgATP2-
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pH 7.5, 37°C
additional information
additional information
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.22
ATP
Homo sapiens
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-
additional information
additional information
Homo sapiens
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60-120 gating events per min
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0026
CFTRinh-172
Homo sapiens
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pH 7.5, 37°C, inhibition of ATPase activity of mutant DELTAPhe508-CFTR
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.06
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with ATP as substrate
0.4
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G551D mutant, with AMP; G551D mutant, with ATP
0.6
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nucleotide-binding domain 2 of wild type, with ATP
0.7
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nucleotide-binding domain 1 of wild type, with AMP; nucleotide-binding domain 1 of wild type, with ATP; nucleotide-binding domain 2 of wild type, with ADP; nucleotide-binding domain 2 of wild type, with AMP
0.9
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wild type, with AMP
1.2
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wild type, with ATP
1.4
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wild type, with ADP
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.2
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single channel activity assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
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ion channel activity assay at room temperature
23 - 26
27
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ion channel assay at
30
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single channel activity assay at
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
26 - 37
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at 26°C dramatic increase in CFTR protein levels as compared to the protein isolated from the tissue incubated at 37°C
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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expression comparable to the expression in alveolar epithelial type II cell
Manually annotated by BRENDA team
transcript detected
Manually annotated by BRENDA team
transcript detected
Manually annotated by BRENDA team
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apical pits of seawater chloride cells
Manually annotated by BRENDA team
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basolateral localization mainly in the thick ascending limb of Henle‘s loop, distal convoluted tubules and to a lesser extent connecting tubules
Manually annotated by BRENDA team
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peritoneal
Manually annotated by BRENDA team
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freshly excised rectal biopsies
Manually annotated by BRENDA team
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infusion of lactic acid to the perfused hindlimb muscles of anaesthetised rats produces dose-dependent decreases in pH and increases in the interstitial ATP of extensor digitorum longus muscle. Acidosis-induced ATP efflux from the perfused muscle is abolished by inhibitor CFTRinh-172, or glibenclamide. Silencing of the CFTR gene using an siRNA abolishes the acidosis-induced increase inATP release from cultured myoblasts
Manually annotated by BRENDA team
transcript detected
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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F508del CFTR in BHK cells
Manually annotated by BRENDA team
additional information
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the wild-type and G551D CFTR have overlapping postendocytic membrane trafficking. G551D like its wild-type counterpart recycles back to the cell surface and largely avoids lysosomal delivery
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Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
160000
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x * 160000, SDS-PAGE
165000
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SDS-PAGE, mannose rich isoform of CFTR
168200
calculated from cDNA
170000
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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
180000
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x * 180000, untagged CFTR, SDS-PAGE, x * 210000, GFP-tagged CFTR, SDS-PAGE
195000
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SDS-PAGE or immunoprecipitation, complex-glycosylated isoform of CFTR
210000
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x * 180000, untagged CFTR, SDS-PAGE, x * 210000, GFP-tagged CFTR, SDS-PAGE
additional information
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homodimer
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
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
phosphoprotein
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
3D structure constructed by molecular modeling. Residue F508 mediates a tertiary interaction between the surface of nucleotide-binding domain 1 and a cytoplasmic loop in the C-terminal membrane-spanning domain
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by hanging drop method, at 20 A resolution in the xy plane, at 30 A resolution along z plane, two crystal forms, one with a roughly hexagonal profile, the other with an opened-out triangular profile, the two conformations are in presence of a nucleotide, which may be related to the role of CFTR as an ion channel rather than a transporter, and may represent the open and closed states of the channel
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native and selenomethionyl nucleotide-binding domain 1, hanging-drop vapor-diffusion method
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
in cycloheximide-treated clone C9 cells, the expressed GFP-CFTR exhibits a half-life of 48-72 h
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in the absence of ATP, the Gd-HCl concentration to denature half of the proteins is about 2.2 M. A smaller Gd-HCl concentration,1.4 M, is needed to produce the same effect upon the application of 25 nM of 2-pyrimidin-7,8-benzoflavone
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
by Ni-NTA resin
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Ni-NTA matrix and subsequent WGA-agorse affinity step
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nucleotide-binding domain 1 and 2, purified to homogeneity under denaturing conditions
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nucleotide-binding domain 1 of CFTR purified to homogeneity by nickel ion affinity chromatography, followed by Sepharose S200 gel filtration and a second nickel affinity step
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of nucleotide binding domain 1 and nucleotide binding domain 2 from Sf9 cells
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purification from Sf9 membranes
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recombinant FLAG-tagged wild-type CFTR from HEK-293 cells by anti-FLAG and wheat germ agglutinin affinity chromatographies, and gel filtration
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recombinant His-tagged mutant DELTAPhe508 from Sf9 cells by nickel affinity chromatography
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the NBF1+R segment (nucleotide binding domain 1 and regulatory domain) and its mutant forms K464H and K464A
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using Ni-NTA chromatography and gel filtration
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wild-type and mutant enzymes partially by subcellular fractionation
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
C terminally deca-histidine-tagged wild type human CFTR epxressed in baby hamster kidney-21 cells
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CFTR genotyping in the Jewish and Arab population in Israel
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cloned into vector pET28b and expressed in Escherichia coli BL21DE3pLys cells
coexpressed with murine or human epithelial Na+ channel in Xenopus laevis oocytes
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coexpression of CFTR residues 1-414 with residues 433-1480, or residues 1-633 with 668-1480 in Xenopus laevis oocytes, to yield split CFTR channels, that lack most of the insertion or extension, respectively
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expressed in Escherichia coli using as N-terminal His-tagged fusion protein
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expressed in Fischer rat thyroid (FRT) cells
expression in BHK 21 cell
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expression in BHK cell
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expression in BHK cells
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expression in CHO cell
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expression in Escherichia coli; stable expressed in CHO cells and transiently transfected in Sf9 cells
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expression in HeLa cells
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expression in Sf9 cells
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expression in Xenopus laevis
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expression in Xenopus laevis oocytes
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expression in Xenopus oocytes
expression of a construct lacking Cys-residues, in CHO-cells
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expression of a fusion protein of glutathione S-transferase and nucleotide binding domain 1
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expression of a human CFTR variant in which all cysteines had been removed by mutagenesis, in baby hamster kidney cells
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expression of FLAG-tagged wild-type CFTR in HEK-293 cells
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expression of GFP-tagged CFTR in isogenic lung epithelial cell lines
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expression of mutant DELTAPhe508 in BHK cells and as His-tagged protein in Spodoptera frugiperda Sf9 cells
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expression of nucleotide binding domain 1 and nucleotide binding domain 2 separately and together in Sf9 cells
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expression of recombinant NBD1, from residue 394 to residue 672, and NBD2, from residue 1191 to residue 1480, polypeptides in Escherichia coli
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expression of the separate nucleotide-binding domains in Sf9 cell
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expression of wild-type and mutant DELTAF508 in HEK-293 cells, and co-expression of CFTR halves
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expression of wild-type and mutant enzymes in CHO cells
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expression of wild-type and mutant enzymes in CHO cells and in HEK-293 cells
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expression of wild-type and mutant enzymes in HEK-293 cells
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expression of wild-type nucleotide-binding domain 1 und a mutated version, K464A, in Escherichia coli
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full-length and truncated -fusion CFTR cDNAs are cloned into pGEM-4z vector and direct translation in a rabbit reticulocyte lysate system
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overexpression of the 3HA-tagged wild-type enzyme as well as of mutant G551D CFTR and mutant DELTAF508 CFTR in BHK, CFBE and HeLa cells
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phylogenetic analysis and genotyping, expression of wild-type and mutant enzymes in Xenopus laevis oocytes
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phylogenetic analysis, recombinant expression of wild-type and mutant enzymes in CHO-K1 and HEK-293 cells
plasmid pQE60, encoding the CFTR amino acids 645-835 with COOH-terminal 6xHis tag, expressed in Escherichia coli, expression of Flag-wild type CFTR cRNA in Xenopus oocytes
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quantitative PCR-based enzyme expression analysis
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recombinant expression of GFP-tagged wild-type and mutant enzymes in CHO cells
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recombinant expression of wild-type and mutant enzymes in CHO cells
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stable expression of wild-type and mutant DELTANBD2 CFTR in BHK-21 cell membranes
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the CFTR gene is located on chromosome 7q31.31
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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
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transfection of CHO cells
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transient expression of CFTR in RAW macrophages
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transient expression of either wild-type or mutant enzymes in HeLa cell membranes using a vaccinia virus/T7 RNA polymerase expression system
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transient expression of the enzyme in HEK-293T cells
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transient expression of wild-type and mutant enzymes in HeLa cell membranes using a vaccinia virus/T7 RNA polymerase expression system, recombinant expression of wild-type and mutant enzymes in CHO cells and in HEK-293T cells, also using a vaccinia virus-T7 hybrid expression system for the latter cell type
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transient recombinant expression of wild-type and mutant enzymes in HEK-293T cells
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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]-
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
-
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
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
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
-
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/F409L/F4929S/F433L/G550E/R553Q/R555K/H667R
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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
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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
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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
E1371Q
E1371S
-
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
E543C/T996C
-
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
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
-
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
G1349D
-
site-directed mutagenesis, a mutation associated with the genetic disease cystic fibrosis
G134D/F337C
-
site-directed mutagenesis, increased accessibility of the side chain of 338C in the closed state compared to mutant F337C
G134D/T338C
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site-directed mutagenesis, limited accessibility of the side chain of 338C in the closed state compared to mutant T338C
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
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increased ATP washout compared to mutant G551D
G551D/Y1219G
G551D/Y1219I
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increased ATP washout compared to mutant G551D
G551E
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site-directed mutagenesis, the mutant exhibits a similar phenotype like mutant G551D
G551K
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site-directed mutagenesis, the mutant does not exhibit a similar phenotype like mutant G551D
G551S
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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
K1250A
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
L323C
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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
N306C
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site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
P355A
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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
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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
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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
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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
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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
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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
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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
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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
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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
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site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
R334W
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amount of Cl- currents is less than 30% that of the wild-type CFTR
R347A
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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
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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
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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
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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
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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
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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
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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
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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/D993R
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
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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
S307C
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site-directed mutagenesis, the engineered cysteine reacts with intracellular 2-sulfonatoethyl methanethiosulfonate
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
T547C
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the mutant does not show activation of the the CFTR chloride channel activity by Cd2+
V171C/L408C
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the mutation has essentially no influence on gating
W1282X
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mutation in the CFTR gene causing cystic fibrosis
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
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little effect on the sensitivity of the channel opening rate to the concentration of ATP, but shortens the open time constant
W401G/G551D
W401Y
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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
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
Y1219G
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
additional information
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
the guanidine hydrochloride-solubilized and denatured wild-type and mutant NBF1+R proteins can be renatured at 25°C upon rapid dilution with a buffered solution containing glycerol
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
additional information
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