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Biochemistry
2012 Jun 26;5125:5113-24. doi: 10.1021/bi300018e.
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Thermal instability of ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) channel function: protection by single suppressor mutations and inhibiting channel activity.
Liu X, O'Donnell N, Landstrom A, Skach WR, Dawson DC.
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Deletion of Phe508 from cystic fibrosis transmembrane conductance regulator (CFTR) results in a temperature-sensitive folding defect that impairs protein maturation and chloride channel function. Both of these adverse effects, however, can be mitigated to varying extents by second-site suppressor mutations. To better understand the impact of second-site mutations on channel function, we compared the thermal sensitivity of CFTR channels in Xenopus oocytes. CFTR-mediated conductance of oocytes expressing wt or ΔF508 CFTR was stable at 22 °C and increased at 28 °C, a temperature permissive for ΔF508 CFTR expression in mammalian cells. At 37 °C, however, CFTR-mediated conductance was further enhanced, whereas that due to ΔF508 CFTR channels decreased rapidly toward background, a phenomenon referred to here as "thermal inactivation." Thermal inactivation of ΔF508 was mitigated by each of five suppressor mutations, I539T, R553M, G550E, R555K, and R1070W, but each exerted unique effects on the severity of, and recovery from, thermal inactivation. Another mutation, K1250A, known to increase open probability (P(o)) of ΔF508 CFTR channels, exacerbated thermal inactivation. Application of potentiators known to increase P(o) of ΔF508 CFTR channels at room temperature failed to protect channels from inactivation at 37 °C and one, PG-01, actually exacerbated thermal inactivation. Unstimulated ΔF508CFTR channels or those inhibited by CFTR(inh)-172 were partially protected from thermal inactivation, suggesting a possible inverse relationship between thermal stability and gating transitions. Thermal stability of channel function and temperature-sensitive maturation of the mutant protein appear to reflect related, but distinct facets of the ΔF508 CFTR conformational defect, both of which must be addressed by effective therapeutic modalities.
Aleksandrov,
Regulatory insertion removal restores maturation, stability and function of DeltaF508 CFTR.
2010, Pubmed
Aleksandrov,
Regulatory insertion removal restores maturation, stability and function of DeltaF508 CFTR.
2010,
Pubmed Aleksandrov,
Allosteric modulation balances thermodynamic stability and restores function of ΔF508 CFTR.
2012,
Pubmed Al-Nakkash,
A common mechanism for cystic fibrosis transmembrane conductance regulator protein activation by genistein and benzimidazolone analogs.
2001,
Pubmed Andersson,
Activation of CFTR by genistein in human airway epithelial cell lines.
2003,
Pubmed Beadle,
Structural bases of stability-function tradeoffs in enzymes.
2002,
Pubmed Celej,
Protein stability induced by ligand binding correlates with changes in protein flexibility.
2003,
Pubmed Cimmperman,
A quantitative model of thermal stabilization and destabilization of proteins by ligands.
2008,
Pubmed Csanády,
Thermodynamics of CFTR channel gating: a spreading conformational change initiates an irreversible gating cycle.
2006,
Pubmed
,
Xenbase Cui,
The role of cystic fibrosis transmembrane conductance regulator phenylalanine 508 side chain in ion channel gating.
2006,
Pubmed Dalemans,
Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation.
,
Pubmed DeCarvalho,
Mutations in the nucleotide binding domain 1 signature motif region rescue processing and functional defects of cystic fibrosis transmembrane conductance regulator delta f508.
2002,
Pubmed Denning,
Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive.
1992,
Pubmed
,
Xenbase Dong,
Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect.
2012,
Pubmed Gentzsch,
Endocytic trafficking routes of wild type and DeltaF508 cystic fibrosis transmembrane conductance regulator.
2004,
Pubmed He,
Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (CFTR) mediate regulation of channel gating.
2008,
Pubmed He,
Restoration of domain folding and interdomain assembly by second-site suppressors of the DeltaF508 mutation in CFTR.
2010,
Pubmed Heda,
The Delta F508 mutation shortens the biochemical half-life of plasma membrane CFTR in polarized epithelial cells.
2001,
Pubmed Hegedus,
F508del CFTR with two altered RXR motifs escapes from ER quality control but its channel activity is thermally sensitive.
2006,
Pubmed Hoelen,
The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain.
2010,
Pubmed Hwang,
Genistein potentiates wild-type and delta F508-CFTR channel activity.
1997,
Pubmed Kuyucak,
Temperature dependence of conductivity in electrolyte solutions and ionic channels of biological membranes.
1994,
Pubmed Lewis,
Structure and dynamics of NBD1 from CFTR characterized using crystallography and hydrogen/deuterium exchange mass spectrometry.
2010,
Pubmed Liu,
Variable reactivity of an engineered cysteine at position 338 in cystic fibrosis transmembrane conductance regulator reflects different chemical states of the thiol.
2006,
Pubmed
,
Xenbase Liu,
Cystic fibrosis transmembrane conductance regulator: temperature-dependent cysteine reactivity suggests different stable conformers of the conduction pathway.
2011,
Pubmed
,
Xenbase Liu,
CFTR: a cysteine at position 338 in TM6 senses a positive electrostatic potential in the pore.
2004,
Pubmed
,
Xenbase Loo,
The V510D suppressor mutation stabilizes DeltaF508-CFTR at the cell surface.
2010,
Pubmed Ma,
Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion.
2002,
Pubmed Mathews,
The CFTR chloride channel: nucleotide interactions and temperature-dependent gating.
1998,
Pubmed Mendoza,
Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.
2012,
Pubmed Mornon,
Atomic model of human cystic fibrosis transmembrane conductance regulator: membrane-spanning domains and coupling interfaces.
2008,
Pubmed Muanprasat,
Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy.
2004,
Pubmed Okiyoneda,
Peripheral protein quality control removes unfolded CFTR from the plasma membrane.
2010,
Pubmed Ostedgaard,
Processing and function of CFTR-DeltaF508 are species-dependent.
2007,
Pubmed Pedemonte,
Phenylglycine and sulfonamide correctors of defective delta F508 and G551D cystic fibrosis transmembrane conductance regulator chloride-channel gating.
2005,
Pubmed Pissarra,
Solubilizing mutations used to crystallize one CFTR domain attenuate the trafficking and channel defects caused by the major cystic fibrosis mutation.
2008,
Pubmed Protasevich,
Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1.
2010,
Pubmed Qu,
Localization and suppression of a kinetic defect in cystic fibrosis transmembrane conductance regulator folding.
1997,
Pubmed Rabeh,
Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function.
2012,
Pubmed Roxo-Rosa,
Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms.
2006,
Pubmed Serohijos,
Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function.
2008,
Pubmed Serrano,
CFTR: Ligand exchange between a permeant anion ([Au(CN)2]-) and an engineered cysteine (T338C) blocks the pore.
2006,
Pubmed
,
Xenbase Sharma,
Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes.
2004,
Pubmed Sharma,
Conformational and temperature-sensitive stability defects of the delta F508 cystic fibrosis transmembrane conductance regulator in post-endoplasmic reticulum compartments.
2001,
Pubmed Shen,
Discovery of potent ligands for estrogen receptor beta by structure-based virtual screening.
2010,
Pubmed Sheppard,
Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents.
1992,
Pubmed Sheppard,
Mechanism of glibenclamide inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in a murine cell line.
1997,
Pubmed Shoichet,
A relationship between protein stability and protein function.
1995,
Pubmed Slaymaker,
Correlation of inhibitor effects on enzyme activity and thermal stability for the integral membrane protein fatty acid amide hydrolase.
2008,
Pubmed Smith,
CFTR: covalent and noncovalent modification suggests a role for fixed charges in anion conduction.
2001,
Pubmed
,
Xenbase Taverna,
Why are proteins marginally stable?
2002,
Pubmed Teem,
Identification of revertants for the cystic fibrosis delta F508 mutation using STE6-CFTR chimeras in yeast.
1993,
Pubmed Teem,
Mutation of R555 in CFTR-delta F508 enhances function and partially corrects defective processing.
1996,
Pubmed Thibodeau,
The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis.
2010,
Pubmed Tokuriki,
How protein stability and new functions trade off.
2008,
Pubmed Van Goor,
Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules.
2006,
Pubmed Varga,
Enhanced cell-surface stability of rescued DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) by pharmacological chaperones.
2008,
Pubmed Waldron,
Stabilization of proteins by ligand binding: application to drug screening and determination of unfolding energetics.
2003,
Pubmed Wang,
Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis.
2010,
Pubmed Wang,
Deletion of phenylalanine 508 causes attenuated phosphorylation-dependent activation of CFTR chloride channels.
2000,
Pubmed Wang,
Thermally unstable gating of the most common cystic fibrosis mutant channel (ΔF508): "rescue" by suppressor mutations in nucleotide binding domain 1 and by constitutive mutations in the cytosolic loops.
2011,
Pubmed Xiong,
Structural cues involved in endoplasmic reticulum degradation of G85E and G91R mutant cystic fibrosis transmembrane conductance regulator.
1997,
Pubmed
,
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