CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) is a unique ABC transporter family member that functions as a phosphorylation- and ATP-regulated anion channel rather than an active pump. It primarily conducts chloride and bicarbonate ions across epithelial cell apical membranes, playing critical roles in fluid secretion and mucociliary clearance in airways, digestive enzyme secretion in pancreas, and salt balance in sweat glands. CFTR requires PKA phosphorylation of its regulatory R domain and ATP binding/hydrolysis at its nucleotide-binding domains for channel gating. Loss-of-function mutations cause cystic fibrosis, characterized by thick mucus in lungs, pancreatic insufficiency, elevated sweat chloride, and male infertility due to vas deferens absence. The most common mutation is ΞF508, which causes protein misfolding and ER retention. CFTR also regulates other ion channels including ENaC and interacts with SLC26 anion exchangers to coordinate epithelial ion transport.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005260 intracellularly ATP-gated chloride channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: This IBA annotation accurately captures CFTR's primary molecular function as an ATP-gated anion channel requiring intracellular ATP binding and hydrolysis for channel gating. This function is well-supported by extensive structural and functional studies showing ATP binding at NBDs drives channel opening. Reason: The term GO:0005260 precisely describes CFTR's unique mechanism among ABC transporters - it functions as a phosphorylation- and nucleotide-regulated anion channel rather than an active pump. The channel requires PKA phosphorylation and ATP binding/hydrolysis at its nucleotide-binding domains for gating cycles. This annotation, based on phylogenetic inference (IBA), correctly identifies the core molecular function. Supporting Evidence: PMID:8910473 ATPase activity of the cystic fibrosis transmembrane conductance regulator PMID:11524016 A monomer is the minimum functional unit required for channel and ATPase activity of the cystic fibrosis transmembrane conductance regulator file:human/CFTR/CFTR-deep-research.md See deep research file for comprehensive analysis |
| GO:0005254 chloride channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR as a chloride channel, which is accurate but less specific than GO:0005260. CFTR does function as a chloride channel, conducting Cl- ions down their electrochemical gradient when open. Reason: While GO:0005254 is correct, it lacks the specificity of GO:0005260 which captures the ATP-gating mechanism. However, as an automated annotation it appropriately identifies the chloride channel function. This term is acceptable as it represents a parent term of the more specific ATP-gated function. The channel primarily mediates passive chloride ion conductance across epithelial cell membranes. Supporting Evidence: PMID:15010471 Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-) PMID:11524016 functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | MODIFY | Summary: This IEA annotation based on UniProt keyword mapping correctly identifies CFTR's nucleotide binding capability but is overly generic. CFTR specifically binds and hydrolyzes ATP at its two nucleotide-binding domains to drive channel gating. Reason: While nucleotide binding is correct, this annotation should be more specific. CFTR specifically binds ATP (not just any nucleotide) at its NBD1 and NBD2 domains. ATP binding promotes NBD dimerization triggering channel opening, while ATP hydrolysis allows channel closure. The generic "nucleotide binding" term fails to capture this ATP-specific requirement for CFTR function. Proposed replacements: ATP binding Supporting Evidence: PMID:8910473 In this study, we report the first measurements of the rate of ATP hydrolysis by purified, reconstituted CFTR PMID:10581360 Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator |
| GO:0005260 intracellularly ATP-gated chloride channel activity | IEA GO_REF:0000003 | ACCEPT | Summary: This IEA annotation based on Enzyme Commission mapping correctly identifies CFTR's ATP-gated chloride channel activity. This duplicates the IBA annotation but from a different evidence source. Reason: The annotation accurately captures CFTR's primary molecular function. Even though this duplicates another annotation with different evidence code, both are valid as they derive from independent inference methods (EC mapping vs phylogenetic inference). The EC number 5.6.1.6 correctly maps to CFTR's channel conductance-controlling ATPase activity. Supporting Evidence: PMID:8910473 ATPase activity of the cystic fibrosis transmembrane conductance regulator |
| GO:0005515 protein binding | IPI PMID:12369822 The down regulated in adenoma (dra) gene product binds to th... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR binding to DRA (SLC26A3), a bicarbonate/chloride exchanger that functionally couples with CFTR for coordinated anion transport in intestinal epithelia. This interaction is physiologically relevant for fluid secretion. Reason: While protein binding is too generic, this specific interaction with DRA/SLC26A3 is functionally important for coordinating chloride and bicarbonate transport in epithelia. The interaction allows coupling of CFTR chloride secretion with DRA-mediated Cl-/HCO3- exchange. However, protein binding itself is not CFTR's core molecular function - the core function is the ATP-gated channel activity. Supporting Evidence: PMID:12369822 The down regulated in adenoma (dra) gene product binds to the second PDZ domain of the NHE3 kinase A regulatory protein (E3KARP), potentially linking intestinal Cl-/HCO3- exchange to Na+/H+ exchange |
| GO:0005515 protein binding | IPI PMID:12471024 The PDZ-binding chloride channel ClC-3B localizes to the Gol... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with ClC-3B chloride channel, which localizes to Golgi and associates with CFTR-interacting PDZ proteins, suggesting a role in CFTR trafficking or regulation. Reason: The interaction with ClC-3B represents a regulatory relationship between chloride channels. While functionally relevant for CFTR trafficking through the Golgi, protein binding is not CFTR's primary molecular function. The generic protein binding term fails to capture the specific nature of this channel-channel interaction. Supporting Evidence: PMID:12471024 The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins |
| GO:0005515 protein binding | IPI PMID:14679199 Inhibitory regulation of cystic fibrosis transmembrane condu... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with Shank2, a PDZ-domain containing scaffolding protein that negatively regulates CFTR anion-transporting activities. Reason: Shank2 binding represents a regulatory interaction that modulates CFTR channel activity. While this interaction is functionally important for controlling CFTR activity, the generic protein binding term is not informative about CFTR's core molecular function as an ATP-gated chloride channel. This represents a regulatory mechanism rather than core function. Supporting Evidence: PMID:14679199 Inhibitory regulation of cystic fibrosis transmembrane conductance regulator anion-transporting activities by Shank2 |
| GO:0005515 protein binding | IPI PMID:16203867 Lysophosphatidic acid inhibits cholera toxin-induced secreto... | KEEP AS NON CORE | Summary: This IPI annotation documents protein interactions involved in lysophosphatidic acid inhibition of CFTR-mediated secretory diarrhea, likely involving regulatory proteins that modulate CFTR activity during cholera toxin response. Reason: This interaction represents a regulatory mechanism controlling CFTR activity in pathological conditions (secretory diarrhea). While physiologically relevant for disease modulation, protein binding is not CFTR's core molecular function. The annotation captures disease-relevant regulatory interactions but uses an overly generic term. Supporting Evidence: PMID:16203867 Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions |
| GO:0005515 protein binding | IPI PMID:16546175 Rescue of functional delF508-CFTR channels in cystic fibrosi... | KEEP AS NON CORE | Summary: This IPI annotation likely documents interactions relevant to miglustat rescue of ΞF508-CFTR, possibly involving chaperones or trafficking proteins that help restore mutant CFTR function. Reason: This represents therapeutic rescue-related protein interactions for the most common CF mutation (ΞF508). While important for understanding CF treatment, these interactions are not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic protein binding term provides minimal functional information. Supporting Evidence: PMID:16546175 Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat |
| GO:0005515 protein binding | IPI PMID:16901789 Sequential quality-control checkpoints triage misfolded cyst... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interactions with quality control machinery including chaperones and ERAD components that triage misfolded CFTR, particularly relevant for ΞF508-CFTR processing. Reason: These interactions with cellular quality control machinery are critical for CFTR biogenesis and trafficking, especially for understanding CF pathogenesis. However, these represent cellular processing mechanisms rather than CFTR's core molecular function as an ATP-gated chloride channel. The generic term lacks specificity about the nature of these quality control interactions. Supporting Evidence: PMID:16901789 Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator |
| GO:0005515 protein binding | IPI PMID:17110338 Hsp90 cochaperone Aha1 downregulation rescues misfolding of ... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with Aha1, an Hsp90 cochaperone whose downregulation can rescue misfolded ΞF508-CFTR, representing a therapeutic target for CF. Reason: The interaction with Aha1/Hsp90 machinery is important for CFTR folding and represents a potential therapeutic target. However, chaperone interactions are part of protein biogenesis rather than CFTR's core molecular function as an ATP-gated chloride channel. This annotation captures disease-relevant interactions but uses an uninformative generic term. Supporting Evidence: PMID:17110338 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis |
| GO:0005515 protein binding | IPI PMID:17244609 Dynamic regulation of cystic fibrosis transmembrane conducta... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interactions with molecular adaptors that dynamically regulate CFTR trafficking and membrane localization through competitive binding mechanisms. Reason: These adaptor protein interactions regulate CFTR surface expression and trafficking, which is physiologically important. However, these regulatory interactions are not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic protein binding term fails to convey the specific regulatory nature of these interactions. Supporting Evidence: PMID:17244609 Dynamic regulation of cystic fibrosis transmembrane conductance regulator by competitive interactions of molecular adaptors |
| GO:0005515 protein binding | IPI PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotra... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with BAP31, which promotes retrotranslocation of misfolded ΞF508-CFTR via the derlin-1 ERAD complex. Reason: The interaction with BAP31 is part of the ER quality control system that recognizes and degrades misfolded CFTR, particularly relevant for ΞF508-CFTR in CF. While important for understanding CFTR biogenesis and CF pathogenesis, this represents a protein quality control mechanism rather than CFTR's core function as an ATP-gated chloride channel. Supporting Evidence: PMID:18555783 BAP31 interacts with Sec61 translocons and promotes retrotranslocation of CFTRΞF508 via the derlin-1 complex |
| GO:0005515 protein binding | IPI PMID:19465887 The ER-resident ubiquitin-specific protease 19 participates ... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with USP19, an ER-resident deubiquitinase that participates in the unfolded protein response and can rescue ERAD substrates including misfolded CFTR. Reason: USP19 interaction represents part of the ER protein quality control system that can rescue misfolded CFTR from degradation. While relevant for CF therapeutics and CFTR biogenesis, this represents a cellular quality control mechanism rather than CFTR's core molecular function as an ATP-gated chloride channel. The generic protein binding term fails to convey the specific nature of this quality control interaction. Supporting Evidence: PMID:19465887 The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates |
| GO:0005515 protein binding | IPI PMID:19878303 Deletion of Phe508 in the first nucleotide-binding domain of... | KEEP AS NON CORE | Summary: This IPI annotation documents increased affinity of ΞF508-CFTR for Hsc70 chaperone due to the deletion in NBD1, contributing to misfolding and retention of the mutant protein. Reason: The enhanced interaction with Hsc70 chaperone is a consequence of the ΞF508 mutation and contributes to CF pathogenesis by promoting ER retention. While crucial for understanding disease mechanisms, chaperone interactions represent protein folding quality control rather than CFTR's core function as an ATP-gated chloride channel. This is a disease-state interaction, not a core functional property. Supporting Evidence: PMID:19878303 Deletion of Phe508 in the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator increases its affinity for the heat shock cognate 70 chaperone |
| GO:0005515 protein binding | IPI PMID:21455491 A Pseudomonas aeruginosa toxin that hijacks the host ubiquit... | KEEP AS NON CORE | Summary: This IPI annotation documents interaction with Cif, a Pseudomonas aeruginosa virulence factor that hijacks the host ubiquitin system to promote CFTR degradation during infection. Reason: This represents a pathogen-host interaction where P. aeruginosa Cif toxin targets CFTR for degradation, contributing to CF lung pathology. While important for understanding CF-associated infections, this is a pathological interaction exploited by bacteria, not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic term fails to convey this is a virulence factor interaction. Supporting Evidence: PMID:21455491 A Pseudomonas aeruginosa toxin that hijacks the host ubiquitin proteolytic system |
| GO:0005515 protein binding | IPI PMID:21884936 Rescue of ΞF508-CFTR trafficking via a GRASP-dependent uncon... | KEEP AS NON CORE | Summary: This IPI annotation documents interactions involved in GRASP-dependent unconventional secretion that can rescue ΞF508-CFTR trafficking by bypassing the Golgi. Reason: These interactions are part of an unconventional secretion pathway that can rescue misfolded CFTR. While therapeutically relevant for CF, this represents an alternative trafficking mechanism rather than CFTR's core function as an ATP-gated chloride channel. The generic protein binding term inadequately describes these specialized trafficking interactions. Supporting Evidence: PMID:21884936 Rescue of ΞF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway |
| GO:0005515 protein binding | IPI PMID:22038833 Disruption of cytokeratin-8 interaction with F508del-CFTR co... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with cytokeratin-8, where disrupting this interaction can correct ΞF508-CFTR functional defects. Reason: The cytokeratin-8 interaction affects CFTR stability and function, with disruption of this interaction offering therapeutic potential for ΞF508-CFTR. While relevant for CFTR regulation and CF therapeutics, cytoskeletal interactions are supportive rather than core to CFTR's primary function as an ATP-gated chloride channel. The generic term fails to specify this is a cytoskeletal interaction. Supporting Evidence: PMID:22038833 Disruption of cytokeratin-8 interaction with F508del-CFTR corrects its functional defect |
| GO:0005515 protein binding | IPI PMID:22121115 The testis anion transporter TAT1 (SLC26A8) physically and f... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with TAT1/SLC26A8, a testis anion transporter important for sperm capacitation, suggesting coordinated anion transport in male reproduction. Reason: The interaction with TAT1/SLC26A8 represents functional coupling between anion transporters in the male reproductive tract. While physiologically important for fertility, this tissue-specific regulatory interaction is not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic protein binding term fails to convey this is a specialized reproductive system interaction. Supporting Evidence: PMID:22121115 The testis anion transporter TAT1 (SLC26A8) physically and functionally interacts with the cystic fibrosis transmembrane conductance regulator channel: a potential role during sperm capacitation |
| GO:0005515 protein binding | IPI PMID:22768251 Proteomic identification of calumenin as a G551D-CFTR associ... | KEEP AS NON CORE | Summary: This IPI annotation identifies calumenin as a G551D-CFTR associated protein, relevant for understanding this gating mutation that causes CF with preserved protein expression. Reason: Calumenin interaction with G551D-CFTR may influence the processing or function of this gating mutant. While relevant for understanding genotype-specific CF mechanisms, this represents a mutation-specific interaction rather than CFTR's core function as an ATP-gated chloride channel. The generic term provides no information about the nature of this ER/calcium-binding protein interaction. Supporting Evidence: PMID:22768251 Proteomic identification of calumenin as a G551D-CFTR associated protein |
| GO:0005515 protein binding | IPI PMID:25661196 SERCA and PMCA pumps contribute to the deregulation of Ca2+ ... | KEEP AS NON CORE | Summary: This IPI annotation likely documents CFTR interactions related to calcium homeostasis, as the study shows SERCA and PMCA pumps contribute to deregulated Ca2+ in CF epithelia. Reason: Interactions affecting calcium homeostasis in CF epithelia represent secondary consequences of CFTR dysfunction rather than direct protein binding. While important for understanding CF pathophysiology, these interactions are not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic term fails to specify the nature of these calcium-regulatory interactions. Supporting Evidence: PMID:25661196 SERCA and PMCA pumps contribute to the deregulation of Ca2+ homeostasis in human CF epithelial cells |
| GO:0005515 protein binding | IPI PMID:25712891 G551D-CFTR needs more bound actin than wild-type CFTR to mai... | KEEP AS NON CORE | Summary: This IPI annotation documents enhanced actin binding requirement for G551D-CFTR to maintain plasma membrane localization compared to wild-type CFTR. Reason: The interaction with actin cytoskeleton is important for CFTR membrane stability, with G551D-CFTR showing increased dependence on actin binding. While relevant for understanding mutation-specific effects, cytoskeletal interactions support but are not core to CFTR's primary function as an ATP-gated chloride channel. The generic term fails to identify this as an actin interaction. Supporting Evidence: PMID:25712891 G551D-CFTR needs more bound actin than wild-type CFTR to maintain its presence in plasma membranes |
| GO:0005515 protein binding | IPI PMID:26618866 βF508 CFTR interactome remodelling promotes rescue of cystic... | KEEP AS NON CORE | Summary: This IPI annotation documents ΞF508-CFTR interactome remodeling that promotes rescue of the mutant protein, identifying therapeutic targets for CF. Reason: This represents the altered protein interaction network of ΞF508-CFTR and how remodeling these interactions can rescue mutant function. While crucial for CF therapeutic development, these are disease-state interactions rather than CFTR's core function as an ATP-gated chloride channel. The generic term provides no information about the complex interactome changes involved. Supporting Evidence: PMID:26618866 βf508 cftr interactome remodelling promotes rescue of cystic fibrosis |
| GO:0005515 protein binding | IPI PMID:27092946 Investigating CFTR and KCa3.1 Protein/Protein Interactions. | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with KCa3.1 calcium-activated potassium channel, suggesting coordinated ion transport mechanisms in epithelia. Reason: The interaction with KCa3.1 represents functional coupling between chloride and potassium channels important for driving epithelial fluid secretion. While physiologically relevant for coordinated ion transport, this regulatory interaction is not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic term fails to convey this is an ion channel partnership. Supporting Evidence: PMID:27092946 Investigating CFTR and KCa3.1 Protein/Protein Interactions |
| GO:0005515 protein binding | IPI PMID:28360110 The CFTR trafficking mutation F508del inhibits the constitut... | KEEP AS NON CORE | Summary: This IPI annotation shows ΞF508-CFTR trafficking mutation inhibits the constitutive activity of SLC26A9, demonstrating functional consequences of CFTR misfolding on partner proteins. Reason: This interaction shows how ΞF508-CFTR mutation affects SLC26A9 function, illustrating disease mechanisms where mutant CFTR disrupts partner anion channels. While important for CF pathophysiology, this represents a pathological interaction consequence rather than CFTR's core function as an ATP-gated chloride channel. The generic term fails to convey the functional inhibition aspect. Supporting Evidence: PMID:28360110 The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9 |
| GO:0005515 protein binding | IPI PMID:29924966 A Proteomic Variant Approach (ProVarA) for Personalized Medi... | KEEP AS NON CORE | Summary: This IPI annotation from a proteomic variant approach study identifies protein interactions relevant for personalized medicine approaches in CF and other diseases. Reason: This represents proteomic-scale interaction mapping for personalized medicine applications. While useful for understanding CFTR's interaction network, these broad proteomic interactions are not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic term provides no specific functional information about individual interactions identified. Supporting Evidence: PMID:29924966 A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease |
| GO:0006695 cholesterol biosynthetic process | IEA GO_REF:0000107 | REMOVE | Summary: This IEA annotation incorrectly assigns CFTR to cholesterol biosynthesis based on ortholog transfer. CFTR is a chloride channel with no enzymatic role in cholesterol synthesis pathways. Reason: This annotation is clearly erroneous. CFTR is an ATP-gated chloride channel with no biochemical role in cholesterol biosynthesis. This appears to be a false positive from automated ortholog annotation transfer. There is no evidence in the literature supporting CFTR involvement in cholesterol synthesis - its only connection to cholesterol is through membrane organization and lipid raft association, not biosynthesis. Supporting Evidence: PMID:11524016 A monomer is the minimum functional unit required for channel and ATPase activity of the cystic fibrosis transmembrane conductance regulator |
| GO:0030301 cholesterol transport | IEA GO_REF:0000107 | REMOVE | Summary: This IEA annotation incorrectly assigns CFTR to cholesterol transport based on ortholog transfer. CFTR transports chloride and bicarbonate ions, not cholesterol. Reason: This annotation is incorrect. CFTR is an anion channel that transports chloride and bicarbonate ions, not cholesterol. While CFTR may localize to cholesterol-rich membrane microdomains (lipid rafts), it does not transport cholesterol itself. This appears to be another false positive from automated annotation transfer, possibly confused with other ABC transporters that do transport lipids. Supporting Evidence: PMID:15010471 dynamic control of CFTR Cl(-)/HCO(3)(-) permeability ratio, which is regulated by external Cl(-) PMID:19019741 Mechanism of direct bicarbonate transport by the CFTR anion channel |
| GO:0051649 establishment of localization in cell | IEA GO_REF:0000107 | REMOVE | Summary: This IEA annotation is overly vague. While CFTR does establish ion gradients and regulate fluid localization through its channel activity, this generic term provides minimal functional information. Reason: This annotation is too generic to be informative. While technically CFTR does contribute to establishing ion localization across membranes, this vague term fails to capture CFTR's specific function as an ATP-gated chloride channel. More specific terms like "chloride transmembrane transport" (GO:1902476) better describe CFTR's actual function. Generic cellular localization terms add no value when specific transport functions are known. Proposed replacements: chloride transmembrane transport Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions |
| GO:0160133 bicarbonate channel activity | IDA PMID:19019741 Mechanism of direct bicarbonate transport by the CFTR anion ... | NEW | Summary: CFTR directly transports bicarbonate ions through its anion-selective pore, with HCO3-/Cl- selectivity dynamically regulated by external chloride concentration. This function is critical for pancreatic secretion, airway surface liquid pH, and male fertility. Reason: This core function is missing from the existing annotations. CFTR transports both chloride and bicarbonate ions, with bicarbonate transport being essential for multiple physiological processes including pancreatic enzyme secretion, airway mucus properties, and sperm capacitation. The bicarbonate conductance is not secondary to chloride transport but occurs directly through the CFTR pore. This should be annotated with IDA evidence based on multiple publications. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions PMID:15010471 dynamic control of CFTR Cl(-)/HCO(3)(-) permeability ratio, which is regulated by external Cl(-) |
| GO:2000649 regulation of sodium ion transmembrane transporter activity | IMP PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores no... | NEW | Summary: CFTR negatively regulates ENaC (epithelial sodium channel) activity, preventing excessive sodium absorption and maintaining proper airway surface liquid hydration. Loss of this regulation in CF leads to sodium hyperabsorption and mucus dehydration. Reason: This critical regulatory function is missing from existing annotations. CFTR inhibits ENaC through multiple mechanisms, and loss of this inhibition in CF patients leads to sodium hyperabsorption, dehydrated mucus, and impaired mucociliary clearance. This regulation is essential for maintaining airway surface liquid homeostasis and represents a core physiological function of CFTR beyond its channel activity. Supporting Evidence: PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium |
| GO:0005515 protein binding | IPI PMID:29393851 Gq activity- and Ξ²-arrestin-1 scaffolding-mediated ADGRG2/CF... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with ADGRG2 (adhesion GPCR G2) required for male fertility, involving both Gq activity and Ξ²-arrestin-1 scaffolding. Reason: The ADGRG2/CFTR coupling is essential for male fertility, representing a specialized reproductive function. While physiologically important in the male reproductive tract, this tissue-specific regulatory interaction is not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic term fails to convey this is a GPCR-channel interaction critical for reproduction. Supporting Evidence: PMID:29393851 Gq activity- and Ξ²-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility |
| GO:0005515 protein binding | IPI PMID:23818989 Ubiquitination and degradation of CFTR by the E3 ubiquitin l... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR degradation by E3 ubiquitin ligase MARCH2 through association with adaptor proteins CAL and STX6, representing a protein degradation pathway. Reason: The interaction with MARCH2 E3 ligase and adaptors represents a degradation pathway controlling CFTR levels. While important for CFTR homeostasis and regulation, protein degradation mechanisms are not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic term fails to specify this is an E3 ligase-mediated degradation interaction. Supporting Evidence: PMID:23818989 Ubiquitination and degradation of CFTR by the E3 ubiquitin ligase MARCH2 through its association with adaptor proteins CAL and STX6 |
| GO:0005254 chloride channel activity | IDA PMID:15010471 Dynamic control of cystic fibrosis transmembrane conductance... | ACCEPT | Summary: This IDA annotation with direct experimental evidence confirms CFTR's chloride channel activity, specifically demonstrating dynamic control of Cl-/HCO3- selectivity by external chloride concentration. Reason: Strong experimental evidence directly demonstrates CFTR's chloride channel activity. The referenced study shows CFTR mediates both chloride and bicarbonate transport, with selectivity controlled by external chloride concentration. While GO:0005260 (ATP-gated) is more specific, this annotation correctly captures the fundamental chloride channel function with solid experimental support. Supporting Evidence: PMID:15010471 Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-) |
| GO:0005254 chloride channel activity | IDA PMID:19019741 Mechanism of direct bicarbonate transport by the CFTR anion ... | ACCEPT | Summary: This IDA annotation provides direct experimental evidence for CFTR's chloride channel activity, with the study specifically demonstrating the mechanism of direct bicarbonate transport through the CFTR pore. Reason: Solid experimental evidence demonstrates CFTR functions as a chloride channel that also conducts bicarbonate ions. The study shows CFTR transports HCO3- directly through its pore rather than through a coupled mechanism, confirming its role as an anion-selective channel. This annotation accurately reflects CFTR's demonstrated chloride channel activity. Supporting Evidence: PMID:19019741 Mechanism of direct bicarbonate transport by the CFTR anion channel |
| GO:0005254 chloride channel activity | IMP PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores no... | ACCEPT | Summary: This IMP annotation uses mutant phenotype evidence showing that restoring CFTR to 25% of epithelial cells restores normal mucus transport rates, confirming CFTR's chloride channel function in airway physiology. Reason: The mutant phenotype evidence clearly demonstrates CFTR's chloride channel activity is essential for normal mucus transport in airways. The study shows a direct relationship between CFTR channel function and physiological mucus clearance, with partial restoration being sufficient for normal function. This supports CFTR's role as a chloride channel critical for airway surface liquid homeostasis. Supporting Evidence: PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium |
| GO:0005254 chloride channel activity | IDA PMID:11524016 A monomer is the minimum functional unit required for channe... | ACCEPT | Summary: This IDA annotation provides direct experimental evidence that a CFTR monomer is the minimum functional unit for chloride channel activity, definitively establishing CFTR's channel function. Reason: Strong experimental evidence demonstrates that CFTR functions as a chloride channel, with a monomer being sufficient for both channel and ATPase activity. This landmark study established that unlike other ABC transporters that function as dimers, CFTR operates as a monomeric channel. The annotation accurately captures CFTR's demonstrated chloride channel activity. Supporting Evidence: PMID:11524016 A monomer is the minimum functional unit required for channel and ATPase activity of the cystic fibrosis transmembrane conductance regulator |
| GO:0005260 intracellularly ATP-gated chloride channel activity | IMP PMID:8910473 ATPase activity of the cystic fibrosis transmembrane conduct... | ACCEPT | Summary: This IMP annotation with mutant phenotype evidence demonstrates CFTR's ATP-gated chloride channel activity, showing that ATPase activity is directly coupled to channel gating. Reason: This seminal study established that CFTR's ATPase activity is essential for its function as an ATP-gated chloride channel. The evidence shows ATP binding and hydrolysis at the nucleotide-binding domains drives channel opening and closing cycles. This annotation precisely captures CFTR's unique mechanism as an ATP-regulated ion channel, distinguishing it from other chloride channels. Supporting Evidence: PMID:8910473 ATPase activity of the cystic fibrosis transmembrane conductance regulator |
| GO:0005254 chloride channel activity | IDA PMID:11707463 A Golgi-associated PDZ domain protein modulates cystic fibro... | ACCEPT | Summary: This IDA annotation documents CFTR chloride channel activity in the context of studying how CAL/GOPC modulates CFTR plasma membrane expression and function. Reason: The study provides direct evidence of CFTR chloride channel activity while investigating PDZ protein interactions. The research shows functional chloride currents mediated by CFTR and how these are modulated by CAL overexpression. This annotation correctly identifies CFTR's chloride channel function with experimental validation. Supporting Evidence: PMID:11707463 Overexpression of CAL reduces CFTR chloride currents in mammalian cells and decreases expression, rate of insertion and half-life of CFTR in the plasma membrane |
| GO:0005254 chloride channel activity | IMP PMID:24885604 CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exo... | ACCEPT | Summary: This IMP annotation demonstrates CFTR chloride channel activity in pancreatic beta cells, showing CFTR contributes to cAMP-amplified exocytosis and insulin secretion alongside ANO1. Reason: Mutant phenotype evidence confirms CFTR functions as a chloride channel in pancreatic beta cells, where it works with ANO1 to regulate insulin secretion. This expands understanding of CFTR's physiological roles beyond epithelial tissues. The annotation accurately reflects CFTR's chloride channel activity in endocrine function. Supporting Evidence: PMID:24885604 CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells |
| GO:0005254 chloride channel activity | IDA PMID:18570918 Endosomal SNARE proteins regulate CFTR activity and traffick... | ACCEPT | Summary: This IDA annotation provides direct evidence that endosomal SNARE proteins regulate CFTR chloride channel activity and trafficking in epithelial cells. Reason: Direct experimental evidence demonstrates CFTR chloride channel activity and shows how SNARE proteins regulate both CFTR trafficking and function. The study establishes that proper CFTR channel activity depends on appropriate membrane trafficking mediated by SNARE proteins. This annotation correctly identifies CFTR's chloride channel function. Supporting Evidence: PMID:18570918 Endosomal SNARE proteins regulate CFTR activity and trafficking in epithelial cells |
| GO:0005515 protein binding | IPI PMID:19289574 SLC26A9 is a constitutively active, CFTR-regulated anion con... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with SLC26A9, a constitutively active CFTR-regulated anion conductance that functionally couples with CFTR in bronchial epithelia. Reason: The interaction with SLC26A9 is functionally important as SLC26A9 provides a CFTR-regulated alternative chloride conductance in airways. This represents a physiologically relevant regulatory relationship where CFTR modulates another anion channel. However, this regulatory interaction is not CFTR's core molecular function as an ATP-gated chloride channel. Supporting Evidence: PMID:19289574 SLC26A9 is a constitutively active, CFTR-regulated anion conductance in human bronchial epithelia |
| GO:0005515 protein binding | IPI PMID:20658517 SLC26A9 stimulates CFTR expression and function in human bro... | KEEP AS NON CORE | Summary: This IPI annotation documents interaction between CFTR and SLC26A9, where SLC26A9 stimulates CFTR expression and function in human bronchial cells, suggesting reciprocal regulation. Reason: This interaction shows bidirectional regulation between CFTR and SLC26A9 anion transporters. While functionally important for coordinated anion transport in airways, this regulatory relationship is not part of CFTR's core molecular function as an ATP-gated chloride channel. The generic protein binding term inadequately describes this specific functional coupling. Supporting Evidence: PMID:20658517 SLC26A9 stimulates CFTR expression and function in human bronchial cell lines |
| GO:0005254 chloride channel activity | IDA PMID:22178883 CFTR and TMEM16A are separate but functionally related Cl- c... | ACCEPT | Summary: This IDA annotation demonstrates CFTR chloride channel activity is distinct from but functionally related to TMEM16A/ANO1 calcium-activated chloride channels in epithelia. Reason: Direct experimental evidence confirms CFTR functions as a chloride channel separate from TMEM16A, though they are functionally related in epithelial chloride secretion. This study clarifies the distinct roles of cAMP-activated (CFTR) versus calcium-activated (TMEM16A) chloride channels. The annotation accurately captures CFTR's chloride channel activity. Supporting Evidence: PMID:22178883 CFTR and TMEM16A are separate but functionally related Cl- channels |
| GO:0005515 protein binding | IPI PMID:22178883 CFTR and TMEM16A are separate but functionally related Cl- c... | KEEP AS NON CORE | Summary: This IPI annotation documents functional interaction between CFTR and TMEM16A chloride channels, showing they work together in epithelial chloride secretion despite being separate channels. Reason: The interaction between CFTR and TMEM16A represents functional coupling between two chloride channel systems in epithelia. While physiologically relevant for coordinated chloride secretion, this interaction is not part of CFTR's core molecular function as an ATP-gated channel. The generic protein binding term fails to capture the specific nature of this channel-channel functional relationship. Supporting Evidence: PMID:22178883 CFTR and TMEM16A are separate but functionally related Cl- channels |
| GO:0005515 protein binding | IPI PMID:11707463 A Golgi-associated PDZ domain protein modulates cystic fibro... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with CAL/GOPC, a Golgi-associated PDZ protein that retains CFTR intracellularly and reduces its plasma membrane expression, competing with NHERF for CFTR binding. Reason: The CAL/GOPC interaction is functionally important for regulating CFTR trafficking and surface expression. CAL competes with NHERF for CFTR's C-terminal PDZ-binding motif, determining whether CFTR is retained intracellularly or reaches the plasma membrane. While physiologically relevant, this represents a trafficking regulatory mechanism rather than CFTR's core channel function. Supporting Evidence: PMID:11707463 CAL modulates the surface expression of CFTR. CAL favors retention of CFTR within the cell, whereas NHE-RF favors surface expression by competing with CAL for the binding of CFTR |
| GO:0005515 protein binding | IPI PMID:15247260 Myosin VI regulates endocytosis of the cystic fibrosis trans... | KEEP AS NON CORE | Summary: This IPI annotation documents CFTR interaction with myosin VI, which regulates CFTR endocytosis from the plasma membrane, controlling surface expression levels. Reason: The myosin VI interaction regulates CFTR endocytosis and membrane turnover. While important for controlling CFTR surface levels and activity, this represents a trafficking mechanism rather than CFTR's core molecular function as an ATP-gated chloride channel. The generic term fails to identify this as a motor protein interaction controlling endocytosis. Supporting Evidence: PMID:15247260 Myosin VI regulates endocytosis of the cystic fibrosis transmembrane conductance regulator |
| GO:0005260 intracellularly ATP-gated chloride channel activity | NAS PMID:11707463 A Golgi-associated PDZ domain protein modulates cystic fibro... | ACCEPT | Summary: This NAS (Non-traceable Author Statement) annotation correctly identifies CFTR's ATP-gated chloride channel activity based on established knowledge referenced in this trafficking study. Reason: While based on author statement rather than direct experimental evidence in this paper, the annotation accurately reflects well-established knowledge about CFTR's ATP-gated chloride channel activity. The paper focuses on trafficking regulation but correctly references CFTR's known molecular function. This annotation captures CFTR's primary functional mechanism. Supporting Evidence: PMID:11707463 CFTR chloride currents in mammalian cells |
| GO:0005254 chloride channel activity | TAS PMID:9931011 Walker mutations reveal loose relationship between catalytic... | ACCEPT | Summary: This TAS annotation based on author statement confirms CFTR chloride channel activity, with the study showing Walker mutations reveal the relationship between catalytic and channel-gating activities. Reason: The study provides strong evidence for CFTR's chloride channel activity by analyzing Walker motif mutations that affect ATP binding/hydrolysis. It demonstrates the coupling between ATPase activity and channel gating, confirming CFTR functions as a chloride channel whose gating is controlled by ATP. This annotation accurately reflects CFTR's established channel function. Supporting Evidence: PMID:9931011 Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR |
| GO:0005260 intracellularly ATP-gated chloride channel activity | TAS PMID:10581360 Differential function of the two nucleotide binding domains ... | ACCEPT | Summary: This TAS annotation demonstrates differential functions of CFTR's two nucleotide binding domains, confirming the ATP-gated nature of the chloride channel. Reason: The study provides detailed evidence for CFTR's ATP-gated chloride channel activity by analyzing the distinct roles of NBD1 and NBD2 in channel gating. It shows how ATP binding and hydrolysis at these domains controls channel opening and closing. This annotation precisely captures CFTR's unique mechanism as an ATP-regulated chloride channel. Supporting Evidence: PMID:10581360 Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator |
| GO:0005515 protein binding | IPI PMID:31324722 Inhibition of calpain 1 restores plasma membrane stability t... | UNDECIDED | Summary: This IPI annotation documents CFTR protein interactions. The publication could not be accessed for detailed review. Reason: Unable to access the referenced publication PMID:31324722 to evaluate the specific protein interactions documented. The annotation uses the generic protein binding term which provides minimal functional insight, but a proper review requires access to the primary literature. Supporting Evidence: PMID:31324722 Epub 2019 Jul 19. Inhibition of calpain 1 restores plasma membrane stability to pharmacologically rescued Phe508del-CFTR variant. |
| GO:0005515 protein binding | IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy... | UNDECIDED | Summary: This IPI annotation documents CFTR protein interactions. The publication could not be accessed for detailed review. Reason: Unable to access the referenced publication PMID:35156780 to evaluate the specific protein interactions documented. The annotation uses the generic protein binding term which provides minimal functional insight, but a proper review requires access to the primary literature. Supporting Evidence: PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system. |
| GO:0140359 ABC-type transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: This IBA annotation classifies CFTR as an ABC-type transporter, which is technically correct as CFTR is a member of the ABC transporter superfamily (ABCC7). However, CFTR is unique among ABC transporters in that it functions as an ion channel rather than an active transporter. Reason: CFTR is a bona fide ABC transporter family member containing two transmembrane domains and two nucleotide-binding domains characteristic of ABC proteins. While CFTR is unique in functioning as an ion channel rather than a transporter, it retains the ABC transporter structural architecture and uses ATP binding/hydrolysis for channel gating [PMID:11524016]. The term is appropriate as it describes CFTR's protein family membership. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: CFTR is a transmembrane protein that spans the plasma membrane and functions as an ion channel. Its membrane topology is essential for its role in anion transport across epithelial cell membranes. Reason: As a transmembrane chloride channel, CFTR must be embedded in the plasma membrane to function properly, with extracellular and intracellular domains positioned on opposite sides of the membrane to enable ion transport. |
| GO:0016323 basolateral plasma membrane | IBA GO_REF:0000033 | REMOVE | Summary: This IBA annotation suggests CFTR localization to the basolateral plasma membrane. However, CFTR is predominantly localized to the apical plasma membrane of epithelial cells where it mediates chloride secretion into luminal spaces. Reason: CFTR is primarily an apical membrane protein in polarized epithelial cells, not basolateral. The apical localization is essential for CFTR's physiological function in secreting chloride and bicarbonate into lumens of airways, intestines, and ducts [PMID:11524016]. Basolateral localization would be inconsistent with CFTR's established role in vectorial ion transport across epithelia. This may represent an erroneous phylogenetic inference. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0006833 water transport | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: This IBA annotation suggests CFTR involvement in water transport. While CFTR indirectly regulates water movement through its control of ion gradients that drive osmotic water flow, CFTR itself does not transport water directly. Reason: CFTR regulates transepithelial water transport indirectly by controlling chloride and bicarbonate secretion, which creates osmotic gradients that drive water movement. This is a downstream physiological consequence of CFTR's chloride channel activity rather than direct water transport. CFTR is an anion channel, not a water channel like aquaporins. The annotation captures a physiologically relevant outcome but may overstate CFTR's direct role. Supporting Evidence: PMID:19019741 CFTR contributes to HCO(3)(-) transport in epithelial cells both directly (by HCO(3)(-) permeation through the channel) and indirectly (by regulating Cl(-)/HCO(3)(-) exchange proteins) |
| GO:0015701 bicarbonate transport | IBA GO_REF:0000033 | ACCEPT | Summary: This IBA annotation correctly identifies CFTR's role in bicarbonate transport. CFTR directly conducts bicarbonate ions through its channel pore, in addition to chloride ions, which is essential for pancreatic secretion, airway surface liquid pH, and sperm capacitation. Reason: CFTR directly transports bicarbonate ions through its anion-selective pore. Patch clamp studies demonstrate that HCO3- permeability is approximately 25% that of Cl- and that both ions share a common transport pathway [PMID:19019741]. Bicarbonate transport by CFTR is critical for pancreatic ductal secretion, airway surface liquid pH regulation, and male fertility. This is a core transport function of CFTR. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions |
| GO:1902476 chloride transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: This IBA annotation correctly identifies CFTR's primary biological process - chloride transmembrane transport. CFTR is the main chloride channel responsible for regulated chloride secretion across epithelial cell membranes. Reason: Chloride transmembrane transport is CFTR's defining biological function. CFTR mediates regulated chloride ion movement across epithelial cell membranes, which is essential for fluid secretion in airways, pancreas, intestine, and other epithelia [PMID:11524016]. This is a core biological process annotation. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005829 cytosol | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: This IBA annotation suggests cytosolic localization. While CFTR has cytosolic domains (NBDs and R domain), CFTR is primarily a membrane protein and cytosol is not its primary localization. Reason: CFTR is an integral membrane protein, not a cytosolic protein. However, portions of CFTR (the nucleotide-binding domains NBD1/NBD2 and the regulatory R domain) do extend into the cytosol. Nascent CFTR also transiently exists in the cytosol during biosynthesis before membrane insertion. This annotation is technically not incorrect but may be misleading about CFTR's primary localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0016324 apical plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: This IBA annotation correctly identifies CFTR's localization to the apical plasma membrane of polarized epithelial cells. This is the correct functional localization for CFTR's role in chloride secretion. Reason: CFTR is specifically targeted to the apical plasma membrane of polarized epithelial cells, where it mediates chloride and bicarbonate secretion into luminal spaces [PMID:11524016]. This apical localization is essential for CFTR's physiological function in fluid secretion and is a core cellular component annotation. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's ATP binding capability. CFTR contains two nucleotide-binding domains (NBD1 and NBD2) that bind ATP to regulate channel gating. Reason: ATP binding is essential for CFTR function. The two NBDs bind ATP, promoting NBD dimerization that opens the channel pore. ATP hydrolysis at NBD2 then allows channel closure [PMID:8910473]. This is a core molecular function of CFTR. Supporting Evidence: PMID:8910473 Following reconstitution the mutant protein exhibited both defective ATP hydrolysis and channel gating, providing direct evidence that CFTR utilizes ATP to gate its channel activity |
| GO:0005634 nucleus | IEA GO_REF:0000044 | REMOVE | Summary: This IEA annotation suggests nuclear localization for CFTR. There is no established evidence that CFTR localizes to or functions in the nucleus. CFTR is a plasma membrane chloride channel. Reason: CFTR is an integral plasma membrane protein that functions as a chloride channel at the cell surface [PMID:11524016]. There is no credible evidence for nuclear localization of full-length CFTR. This appears to be an erroneous computational annotation, possibly from misinterpretation of proteomics data or spurious sequence-based predictions. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: This IEA annotation indicates cytoplasmic localization. While CFTR has cytoplasmic domains and nascent protein is synthesized in the cytoplasm, CFTR's functional localization is at the plasma membrane. Reason: CFTR is primarily a plasma membrane protein. However, newly synthesized CFTR exists in the cytoplasm/ER during biosynthesis, and the large cytoplasmic domains (NBD1, R domain, NBD2) technically extend into the cytoplasm. This annotation is not incorrect but does not represent CFTR's primary functional localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: This IEA annotation identifies ER membrane localization for CFTR. This is correct as CFTR is synthesized and initially folded in the ER membrane before trafficking to the plasma membrane. Reason: CFTR is synthesized as an integral membrane protein in the ER, where it undergoes folding and quality control. Immature CFTR transiently resides in the ER membrane during biosynthesis. ER retention of misfolded CFTR (especially deltaF508-CFTR) is a hallmark of cystic fibrosis pathogenesis. While not CFTR's functional destination, ER membrane localization is part of its normal biogenesis pathway. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's localization to the plasma membrane, which is its primary functional location. Reason: CFTR's functional localization is at the plasma membrane, specifically the apical plasma membrane of epithelial cells, where it mediates chloride and bicarbonate secretion [PMID:11524016]. This is a core cellular component annotation. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's role in ion transport. CFTR transports chloride and bicarbonate ions, which are monoatomic/simple inorganic anions. Reason: CFTR mediates the transport of chloride and bicarbonate ions across epithelial cell membranes [PMID:19019741]. While this term is more general than specific chloride or bicarbonate transport terms, it correctly captures CFTR's core function as an ion channel. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions |
| GO:0006821 chloride transport | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's primary biological process - chloride transport. CFTR is the main chloride channel in epithelial cells. Reason: Chloride transport is CFTR's defining biological function. CFTR mediates regulated chloride ion movement across epithelial cell membranes [PMID:11524016]. This is a core biological process annotation. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0015701 bicarbonate transport | IEA GO_REF:0000117 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's role in bicarbonate transport. CFTR directly conducts bicarbonate ions in addition to chloride ions. Reason: CFTR directly transports bicarbonate through its anion-selective channel pore [PMID:19019741]. Bicarbonate transport by CFTR is essential for pancreatic secretion, airway surface liquid pH, and male fertility. This is a core biological process annotation. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation identifies CFTR as a membrane protein, which is correct but very general. CFTR is an integral membrane protein. Reason: CFTR is an integral membrane protein with multiple membrane-spanning domains [PMID:11524016]. While this term is less specific than plasma membrane or apical plasma membrane, it correctly captures CFTR's membrane association. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR localization to the apical plasma membrane of epithelial cells. Reason: CFTR is specifically targeted to the apical plasma membrane of polarized epithelial cells [PMID:11524016]. This is a core cellular component annotation essential for CFTR's physiological function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0016853 isomerase activity | IEA GO_REF:0000043 | REMOVE | Summary: This IEA annotation suggests isomerase activity for CFTR. This annotation appears erroneous as CFTR is a chloride channel with ATPase activity, not an isomerase. Reason: CFTR is a chloride channel that uses ATP binding and hydrolysis for channel gating [PMID:8910473]. It has no known isomerase activity. This annotation appears to be an incorrect automated transfer, possibly due to misinterpretation of CFTR's EC number 5.6.1.6 (channel-conductance-controlling ATPase), which is in the isomerase class but refers to the conformational changes coupled to ATP hydrolysis, not true isomerase activity. Supporting Evidence: PMID:8910473 Following reconstitution the mutant protein exhibited both defective ATP hydrolysis and channel gating, providing direct evidence that CFTR utilizes ATP to gate its channel activity |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's ATP hydrolysis activity. CFTR hydrolyzes ATP at its nucleotide-binding domains to regulate channel gating. Reason: ATP hydrolysis is essential for CFTR channel gating. Purified reconstituted CFTR has intrinsic ATPase activity required for opening and closing the channel gate [PMID:8910473]. This is a core molecular function of CFTR. Supporting Evidence: PMID:8910473 In this study, we report the first measurements of the rate of ATP hydrolysis by purified, reconstituted CFTR |
| GO:0031901 early endosome membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: This IEA annotation identifies early endosome membrane localization. CFTR does traffic through the endosomal system as part of its recycling pathway between the plasma membrane and intracellular compartments. Reason: CFTR undergoes constitutive endocytosis and recycling. After internalization from the plasma membrane, CFTR is found in early endosomes before being sorted for recycling back to the surface or degradation. This represents a trafficking intermediate rather than CFTR's primary functional localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0034220 monoatomic ion transmembrane transport | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's role in ion transmembrane transport. CFTR transports chloride and bicarbonate ions across membranes. Reason: CFTR mediates transmembrane transport of chloride and bicarbonate ions [PMID:19019741]. While this term is more general than specific anion transport terms, it correctly captures CFTR's fundamental function. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions |
| GO:0034707 chloride channel complex | IEA GO_REF:0000043 | ACCEPT | Summary: This IEA annotation identifies CFTR as part of a chloride channel complex. While CFTR is a chloride channel, the monomeric form is sufficient for function. Reason: CFTR functions as a chloride channel, and while a monomer is sufficient for channel activity [PMID:11524016], CFTR does interact with other proteins (NHERF, SLC26 transporters) to form functional complexes at the cell surface. The term appropriately captures CFTR's role as a chloride channel component. Supporting Evidence: PMID:11524016 CFTR function does not require a multimeric complex for function as we determined that purified, reconstituted CFTR monomers are sufficient to mediate regulated chloride conduction and ATPase activity |
| GO:0055038 recycling endosome membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: This IEA annotation identifies recycling endosome membrane localization. CFTR does transit through recycling endosomes as part of its constitutive endocytic recycling pathway. Reason: CFTR undergoes constitutive endocytosis and recycling between the plasma membrane and intracellular compartments. Recycling endosomes are key intermediates in this trafficking pathway that maintains CFTR surface expression. However, this represents a trafficking compartment rather than CFTR's primary functional localization at the apical plasma membrane. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's involvement in transmembrane transport. CFTR mediates chloride and bicarbonate transport across epithelial cell membranes. Reason: CFTR mediates transmembrane transport of anions (chloride and bicarbonate) [PMID:19019741]. While this is a general term, it correctly captures CFTR's fundamental transport function. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions |
| GO:0098660 obsolete inorganic ion transmembrane transport | IEA GO_REF:0000117 | REMOVE | Summary: This annotation uses an obsolete GO term and should be replaced with current terminology. Reason: This GO term is marked as obsolete. The annotation should use current GO terminology such as GO:0034220 (monoatomic ion transmembrane transport) or more specific terms like GO:1902476 (chloride transmembrane transport). Obsolete terms should not be retained. |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation classifies CFTR as an ABC-type transporter. CFTR is a member of the ABC transporter superfamily (ABCC7) though it uniquely functions as a channel rather than a pump. Reason: CFTR belongs to the ABC transporter superfamily and has the characteristic ABC domain architecture [PMID:11524016]. While CFTR functions as an ion channel rather than an active transporter, the ABC-type transporter activity term appropriately describes its protein family classification. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005515 protein binding | IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ... | UNDECIDED | Summary: This IPI annotation documents CFTR protein interactions. The publication could not be accessed for detailed review. Reason: Unable to access the referenced publication PMID:36012204 to evaluate the specific protein interactions documented. A proper review requires access to the primary literature. Supporting Evidence: PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters. |
| GO:0005515 protein binding | IPI PMID:39009827 Proteome-scale characterisation of motif-based interactome r... | UNDECIDED | Summary: This IPI annotation documents CFTR protein interactions. The publication could not be accessed for detailed review. Reason: Unable to access the referenced publication PMID:39009827 to evaluate the specific protein interactions documented. A proper review requires access to the primary literature. Supporting Evidence: PMID:39009827 2024 Jul 15. Proteome-scale characterisation of motif-based interactome rewiring by disease mutations. |
| GO:0005515 protein binding | IPI PMID:9671706 A C-terminal motif found in the beta2-adrenergic receptor, P... | UNDECIDED | Summary: This IPI annotation documents CFTR protein interactions. The publication could not be accessed for detailed review. Reason: Unable to access the referenced publication PMID:9671706 to evaluate the specific protein interactions documented. A proper review requires access to the primary literature. Supporting Evidence: PMID:9671706 A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins. |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-382556 | ACCEPT | Summary: This TAS annotation from Reactome correctly identifies CFTR's role in transmembrane transport. Reason: CFTR mediates transmembrane transport of chloride and bicarbonate ions [PMID:19019741]. This Reactome annotation correctly captures CFTR's fundamental transport function. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions |
| GO:0005829 cytosol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This IEA annotation suggests cytosolic localization. CFTR is primarily a membrane protein with cytosolic domains. Reason: CFTR is an integral membrane protein, but its NBDs and R domain extend into the cytosol. This annotation is not incorrect but does not represent CFTR's primary functional localization at the plasma membrane. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0015106 bicarbonate transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's bicarbonate transport function. Reason: CFTR directly transports bicarbonate ions through its anion-selective pore [PMID:19019741]. This is a core molecular function of CFTR essential for pancreatic secretion and airway surface liquid pH. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions |
| GO:0015108 chloride transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's chloride transport function. Reason: CFTR is a chloride transmembrane transporter that mediates chloride ion movement across epithelial cell membranes [PMID:11524016]. This is CFTR's primary molecular function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0048240 sperm capacitation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This IEA annotation identifies CFTR's role in sperm capacitation. CFTR is expressed in sperm and required for normal capacitation through bicarbonate transport and pH regulation. Reason: CFTR is expressed in sperm and contributes to capacitation through its bicarbonate transport function, which helps regulate intracellular pH and membrane hyperpolarization. Male infertility due to congenital bilateral absence of vas deferens (CBAVD) is a common CF manifestation. While physiologically important, sperm capacitation is a tissue-specific downstream process rather than CFTR's core molecular function. Supporting Evidence: PMID:19019741 CFTR contributes to HCO(3)(-) transport in epithelial cells both directly (by HCO(3)(-) permeation through the channel) and indirectly |
| GO:0051454 intracellular pH elevation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This IEA annotation suggests CFTR involvement in intracellular pH elevation. CFTR's bicarbonate transport can contribute to pH regulation. Reason: CFTR transports bicarbonate ions, which can affect intracellular pH. In sperm, CFTR-mediated bicarbonate transport contributes to intracellular alkalinization during capacitation. However, this is a downstream physiological consequence of CFTR's bicarbonate transport rather than its primary molecular function. Supporting Evidence: PMID:19019741 CFTR contributes to HCO(3)(-) transport in epithelial cells both directly (by HCO(3)(-) permeation through the channel) and indirectly |
| GO:0060081 membrane hyperpolarization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This IEA annotation suggests CFTR involvement in membrane hyperpolarization. Chloride efflux through CFTR can contribute to membrane potential changes. Reason: CFTR-mediated chloride transport can affect membrane potential. In sperm, CFTR activity contributes to membrane hyperpolarization during capacitation. However, this is an indirect consequence of CFTR's anion channel activity rather than a direct function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0070175 positive regulation of enamel mineralization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This IEA annotation suggests CFTR involvement in enamel mineralization. CFTR is expressed in ameloblasts and contributes to pH regulation during enamel formation. Reason: CFTR is expressed in dental ameloblasts and contributes to the ion transport required for proper enamel mineralization. CF patients can have dental enamel defects. However, enamel mineralization is a tissue-specific downstream process rather than CFTR's core molecular function as an anion channel. Supporting Evidence: PMID:19019741 CFTR contributes to HCO(3)(-) transport in epithelial cells both directly (by HCO(3)(-) permeation through the channel) and indirectly |
| GO:0071320 cellular response to cAMP | IEA GO_REF:0000107 | ACCEPT | Summary: This IEA annotation identifies CFTR's involvement in cellular response to cAMP. CFTR is activated by PKA-mediated phosphorylation in response to elevated cAMP. Reason: CFTR channel activity is directly regulated by cAMP through PKA-mediated phosphorylation of its R domain [PMID:11524016]. This makes CFTR a key effector of cAMP signaling in epithelial cells, where cAMP elevation leads to CFTR-dependent chloride secretion. This annotation correctly captures CFTR's role in the cellular response to cAMP. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0097186 amelogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This IEA annotation suggests CFTR involvement in amelogenesis (enamel formation). CFTR is expressed in ameloblasts and contributes to ion transport during tooth development. Reason: CFTR contributes to amelogenesis through its role in ion transport in developing teeth. Dental enamel defects have been reported in CF patients. However, amelogenesis is a tissue-specific developmental process rather than CFTR's core molecular function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:1902476 chloride transmembrane transport | IEA GO_REF:0000107 | ACCEPT | Summary: This IEA annotation correctly identifies CFTR's primary biological process - chloride transmembrane transport. Reason: Chloride transmembrane transport is CFTR's defining biological function [PMID:11524016]. This is a core biological process annotation. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:1902476 chloride transmembrane transport | IDA PMID:22006324 Anoctamin 6 is an essential component of the outwardly recti... | ACCEPT | Summary: This IDA annotation provides direct experimental evidence for CFTR's chloride transport function. Reason: Direct assay evidence for CFTR-mediated chloride transmembrane transport. This is CFTR's core biological function [PMID:11524016]. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:22006324 Anoctamin 6 is an essential component of the outwardly rectifying chloride channel. |
| GO:0071889 14-3-3 protein binding | EXP PMID:26888287 Characterization and small-molecule stabilization of the mul... | ACCEPT | Summary: This EXP annotation documents CFTR binding to 14-3-3 proteins via its phosphorylated R domain. Reason: The CFTR R domain binds 14-3-3 proteins in a phosphorylation-dependent manner. This interaction enhances CFTR trafficking to the plasma membrane and is therapeutically relevant for correcting deltaF508-CFTR trafficking defects [PMID:26888287]. Supporting Evidence: PMID:26888287 The binding of the 14-3-3 protein to the CFTR regulatory (R) domain has been found to enhance CFTR trafficking to the plasma membrane |
| GO:0071889 14-3-3 protein binding | IMP PMID:26888287 Characterization and small-molecule stabilization of the mul... | ACCEPT | Summary: This IMP annotation provides mutational phenotype evidence for CFTR-14-3-3 binding. Reason: Mutational analysis demonstrates that specific phosphorylation sites in CFTR R domain (especially pS768) are required for 14-3-3 binding, and mutations affecting these sites reduce CFTR trafficking [PMID:26888287]. Supporting Evidence: PMID:26888287 The key binding site of CFTR (pS768) occupies one groove of the 14-3-3 dimer, and a weaker, secondary binding site occupies the other binding groove |
| GO:0071889 14-3-3 protein binding | IPI PMID:26888287 Characterization and small-molecule stabilization of the mul... | ACCEPT | Summary: This IPI annotation documents physical interaction between CFTR and 14-3-3 proteins. Reason: Crystal structures and biochemical assays demonstrate direct physical interaction between CFTR R domain peptides and 14-3-3 proteins [PMID:26888287]. Supporting Evidence: PMID:26888287 Using multiple biochemical assays and crystal structures, we show that the interaction between them is governed by two binding sites |
| GO:0016324 apical plasma membrane | IDA PMID:32487539 TMEM16A deficiency: a potentially fatal neonatal disease res... | ACCEPT | Summary: CFTR functions as an ATP-gated chloride channel specifically localized to the apical plasma membrane of epithelial cells, where it regulates anion secretion and fluid transport across epithelial barriers. Reason: Apical plasma membrane localization is critical for CFTR function as it enables proper directional chloride secretion from epithelial cells into luminal spaces, which is essential for maintaining proper fluid balance in airways, intestines, and other epithelia. Supporting Evidence: PMID:32487539 2020 Jun 2. TMEM16A deficiency: a potentially fatal neonatal disease resulting from impaired chloride currents. |
| GO:0070175 positive regulation of enamel mineralization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: This ISS annotation suggests CFTR involvement in enamel mineralization based on sequence similarity. Reason: CFTR is expressed in ameloblasts and contributes to ion transport during tooth development. However, enamel mineralization is a tissue-specific developmental process rather than CFTR's core molecular function as an anion channel. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0097186 amelogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: This ISS annotation suggests CFTR involvement in amelogenesis based on sequence similarity. Reason: CFTR contributes to amelogenesis through its ion transport function in developing teeth. However, amelogenesis is a tissue-specific developmental process rather than CFTR's core molecular function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:1902476 chloride transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: This ISS annotation identifies CFTR's chloride transport function based on sequence similarity. Reason: Chloride transmembrane transport is CFTR's primary biological function [PMID:11524016]. This is a core annotation. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0017081 chloride channel regulator activity | TAS Reactome:R-HSA-383190 | ACCEPT | Summary: This TAS annotation from Reactome suggests CFTR has chloride channel regulator activity, which is accurate as CFTR regulates other chloride channels like ORCC and ClC channels. Reason: CFTR regulates other chloride channels in addition to functioning as a chloride channel itself. CFTR activation influences the activity of outwardly rectifying chloride channels (ORCC) and other anion transport pathways. This regulatory function is well-established in the CF literature. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0016887 ATP hydrolysis activity | IDA PMID:11524016 A monomer is the minimum functional unit required for channe... | ACCEPT | Summary: This IDA annotation provides direct experimental evidence for CFTR's ATP hydrolysis activity. Reason: Direct assay evidence demonstrates that purified, reconstituted CFTR has intrinsic ATPase activity required for channel gating [PMID:11524016, PMID:8910473]. This is a core molecular function of CFTR. Supporting Evidence: PMID:11524016 purified, reconstituted CFTR monomers are sufficient to mediate regulated chloride conduction and ATPase activity |
| GO:0016887 ATP hydrolysis activity | IDA PMID:8910473 ATPase activity of the cystic fibrosis transmembrane conduct... | ACCEPT | Summary: This IDA annotation provides the first direct measurements of CFTR ATPase activity. Reason: This landmark study [PMID:8910473] provided the first biochemical evidence that CFTR possesses intrinsic ATPase activity. The G551D mutation that resides in a conserved nucleotidase motif caused both defective ATP hydrolysis and channel gating, demonstrating that ATP hydrolysis is essential for CFTR channel function. Supporting Evidence: PMID:8910473 In this study, we report the first measurements of the rate of ATP hydrolysis by purified, reconstituted CFTR |
| GO:0015108 chloride transmembrane transporter activity | TAS Reactome:R-HSA-5678822 | ACCEPT | Summary: This TAS annotation from Reactome correctly identifies CFTR's chloride transport function. Reason: CFTR is a chloride transmembrane transporter that mediates chloride ion movement across epithelial membranes [PMID:11524016]. This is CFTR's core molecular function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0015108 chloride transmembrane transporter activity | TAS Reactome:R-HSA-5678863 | ACCEPT | Summary: This TAS annotation from Reactome correctly identifies CFTR's chloride transport function. Reason: CFTR is a chloride transmembrane transporter [PMID:11524016]. This is CFTR's core molecular function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0043225 obsolete ATPase-coupled inorganic anion transmembrane transporter activity | TAS Reactome:R-HSA-1454916 | REMOVE | Summary: This annotation uses an obsolete GO term and should be replaced with current terminology. Reason: This GO term is marked as obsolete. The annotation should use current GO terminology. Additionally, while CFTR uses ATP for channel gating, it functions as a channel (facilitated diffusion) rather than an ATPase-coupled transporter (active transport). |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868658 | KEEP AS NON CORE | Summary: This TAS annotation from Reactome identifies CFTR in clathrin-coated endocytic vesicle membranes during trafficking. Reason: CFTR undergoes clathrin-mediated endocytosis as part of its constitutive recycling pathway. This represents a trafficking intermediate rather than CFTR's primary functional localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868659 | KEEP AS NON CORE | Summary: This TAS annotation from Reactome identifies CFTR in clathrin-coated endocytic vesicle membranes. Reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling pathway. This is a trafficking intermediate rather than CFTR's primary functional localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868660 | KEEP AS NON CORE | Summary: This TAS annotation from Reactome identifies CFTR in clathrin-coated endocytic vesicle membranes. Reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling pathway. This is a trafficking intermediate. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868661 | KEEP AS NON CORE | Summary: CFTR in clathrin-coated endocytic vesicle membranes during trafficking. Reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling pathway. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8869438 | KEEP AS NON CORE | Summary: CFTR in clathrin-coated endocytic vesicle membranes during trafficking. Reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling pathway. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871193 | KEEP AS NON CORE | Summary: CFTR in clathrin-coated endocytic vesicle membranes during trafficking. Reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling pathway. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871194 | KEEP AS NON CORE | Summary: CFTR in clathrin-coated endocytic vesicle membranes during trafficking. Reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling pathway. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005886 plasma membrane | IDA PMID:28067262 Sec16A is critical for both conventional and unconventional ... | ACCEPT | Summary: Direct experimental evidence for CFTR plasma membrane localization. Reason: CFTR localizes to the plasma membrane where it functions as a chloride channel [PMID:11524016]. Core localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:28067262 Sec16A is critical for both conventional and unconventional secretion of CFTR. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:28067262 Sec16A is critical for both conventional and unconventional ... | KEEP AS NON CORE | Summary: This annotation suggests CFTR involvement in ER stress response. Misfolded CFTR (especially deltaF508) triggers ER stress. Reason: Misfolded CFTR variants trigger ER stress and activate the unfolded protein response. This is particularly relevant for deltaF508-CFTR. However, this reflects CFTR's role as a substrate of ER quality control rather than its primary function as a chloride channel. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:28067262 Sec16A is critical for both conventional and unconventional secretion of CFTR. |
| GO:0005886 plasma membrane | IDA PMID:21884936 Rescue of ΞF508-CFTR trafficking via a GRASP-dependent uncon... | ACCEPT | Summary: Direct experimental evidence for CFTR plasma membrane localization. Reason: CFTR localizes to the plasma membrane where it functions as a chloride channel [PMID:11524016]. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:21884936 Rescue of ΞF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:21884936 Rescue of ΞF508-CFTR trafficking via a GRASP-dependent uncon... | KEEP AS NON CORE | Summary: CFTR involvement in ER stress response related to protein folding. Reason: Misfolded CFTR triggers ER stress. This reflects CFTR's role as a substrate of ER quality control rather than its primary function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:21884936 Rescue of ΞF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway. |
| GO:0106138 Sec61 translocon complex binding | IDA PMID:9792704 The mechanism underlying cystic fibrosis transmembrane condu... | KEEP AS NON CORE | Summary: CFTR binds to Sec61 translocon during its cotranslational insertion into the ER membrane. Reason: CFTR interacts with the Sec61 translocon during membrane insertion in the ER. This is part of CFTR's biogenesis pathway rather than its primary function as a chloride channel. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:9792704 The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes Sec61beta and a cytosolic, deglycosylated intermediary. |
| GO:0051087 protein-folding chaperone binding | IPI PMID:16207813 BAG-2 acts as an inhibitor of the chaperone-associated ubiqu... | KEEP AS NON CORE | Summary: CFTR binds chaperone proteins during its folding in the ER. Reason: CFTR interacts with multiple chaperones (Hsp70, Hsp90, calnexin) during its complex folding process. Chaperone interactions are important for CFTR maturation but represent biogenesis rather than its primary chloride channel function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:16207813 2005 Oct 5. BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | REMOVE | Summary: This annotation suggests nuclear localization for CFTR. There is no evidence CFTR localizes to or functions in the nucleus. Reason: CFTR is a plasma membrane chloride channel with no known nuclear localization or function [PMID:11524016]. This appears to be an erroneous computational annotation. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0005886 plasma membrane | IDA PMID:28130590 Expression of epithelial sodium channel (ENaC) and CFTR in t... | ACCEPT | Summary: Direct experimental evidence for CFTR plasma membrane localization. Reason: CFTR localizes to the plasma membrane where it functions as a chloride channel [PMID:11524016]. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:28130590 Epub 2017 Jan 27. Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages. |
| GO:0016324 apical plasma membrane | IDA PMID:28130590 Expression of epithelial sodium channel (ENaC) and CFTR in t... | ACCEPT | Summary: Direct experimental evidence for CFTR apical plasma membrane localization. Reason: CFTR localizes specifically to the apical plasma membrane of polarized epithelial cells [PMID:11524016]. This is a core localization annotation. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:28130590 Epub 2017 Jan 27. Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages. |
| GO:0005886 plasma membrane | IDA PMID:15010471 Dynamic control of cystic fibrosis transmembrane conductance... | ACCEPT | Summary: Direct experimental evidence for CFTR plasma membrane localization from bicarbonate transport study. Reason: CFTR localizes to the plasma membrane [PMID:11524016, PMID:15010471]. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:15010471 2004 Mar 9. Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-). |
| GO:0015106 bicarbonate transmembrane transporter activity | IDA PMID:15010471 Dynamic control of cystic fibrosis transmembrane conductance... | ACCEPT | Summary: Direct experimental evidence for CFTR bicarbonate transport activity. Reason: CFTR directly conducts bicarbonate ions through its channel pore [PMID:19019741, PMID:15010471]. This is a core molecular function. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions PMID:15010471 2004 Mar 9. Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-). |
| GO:0015106 bicarbonate transmembrane transporter activity | IDA PMID:19019741 Mechanism of direct bicarbonate transport by the CFTR anion ... | ACCEPT | Summary: Direct experimental evidence for CFTR bicarbonate transport using patch clamp. Reason: This study provided direct patch clamp evidence that CFTR conducts bicarbonate with approximately 25% the permeability of chloride [PMID:19019741]. Core molecular function. Supporting Evidence: PMID:19019741 The permeability of HCO(3)(-) was approximately 25% that of Cl(-) and was invariable under all ionic conditions studied |
| GO:0015701 bicarbonate transport | IDA PMID:15010471 Dynamic control of cystic fibrosis transmembrane conductance... | ACCEPT | Summary: Direct evidence for CFTR-mediated bicarbonate transport. Reason: CFTR transports bicarbonate ions [PMID:19019741]. Core biological process. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR PMID:15010471 2004 Mar 9. Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-). |
| GO:0015701 bicarbonate transport | IDA PMID:19019741 Mechanism of direct bicarbonate transport by the CFTR anion ... | ACCEPT | Summary: Direct patch clamp evidence for CFTR-mediated bicarbonate transport. Reason: CFTR transports bicarbonate ions [PMID:19019741]. Core biological process. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR |
| GO:0016324 apical plasma membrane | IMP PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores no... | ACCEPT | Summary: Mutant phenotype evidence for CFTR apical plasma membrane localization. Reason: CFTR localizes to the apical plasma membrane [PMID:11524016]. Core localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:19621064 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. |
| GO:0035377 transepithelial water transport | IMP PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores no... | KEEP AS NON CORE | Summary: CFTR indirectly regulates transepithelial water transport through ion transport. Reason: CFTR controls water movement indirectly by regulating ion gradients that drive osmotic water flow. This is a downstream physiological consequence of CFTR's chloride channel activity. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:19621064 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. |
| GO:0050891 multicellular organismal-level water homeostasis | IMP PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores no... | KEEP AS NON CORE | Summary: CFTR contributes to organismal water homeostasis through epithelial fluid secretion. Reason: CFTR regulates fluid secretion across multiple epithelia, contributing to organismal water balance. This is an indirect, downstream consequence of CFTR's ion channel activity rather than its core function. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:19621064 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. |
| GO:1902476 chloride transmembrane transport | IDA PMID:19019741 Mechanism of direct bicarbonate transport by the CFTR anion ... | ACCEPT | Summary: Direct evidence for CFTR chloride transport from patch clamp studies. Reason: CFTR mediates chloride transmembrane transport [PMID:19019741]. Core biological process. Supporting Evidence: PMID:19019741 Cl(-) and HCO(3)(-) share a common transport pathway in CFTR |
| GO:1902476 chloride transmembrane transport | IMP PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores no... | ACCEPT | Summary: Mutant phenotype evidence for CFTR chloride transport. Reason: CFTR mediates chloride transmembrane transport [PMID:11524016]. Core biological process. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:19621064 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. |
| GO:1904322 cellular response to forskolin | IDA PMID:15010471 Dynamic control of cystic fibrosis transmembrane conductance... | KEEP AS NON CORE | Summary: CFTR responds to forskolin via cAMP-PKA signaling pathway. Reason: Forskolin elevates cAMP, which activates PKA-mediated CFTR phosphorylation and channel opening. This reflects CFTR's role as a cAMP-regulated channel rather than a direct response to forskolin. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:15010471 2004 Mar 9. Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-). |
| GO:1904322 cellular response to forskolin | IDA PMID:19621064 CFTR delivery to 25% of surface epithelial cells restores no... | KEEP AS NON CORE | Summary: CFTR responds to forskolin via cAMP-PKA signaling. Reason: CFTR is activated by forskolin-induced cAMP elevation. This reflects CFTR's cAMP regulation rather than a direct response. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:19621064 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. |
| GO:0005886 plasma membrane | IDA PMID:11524016 A monomer is the minimum functional unit required for channe... | ACCEPT | Summary: Direct evidence for CFTR plasma membrane localization from this key study. Reason: This landmark study demonstrated CFTR functions at the plasma membrane [PMID:11524016]. Core localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells |
| GO:0016020 membrane | IDA PMID:8910473 ATPase activity of the cystic fibrosis transmembrane conduct... | ACCEPT | Summary: CFTR is a membrane protein, demonstrated during ATPase activity studies. Reason: CFTR is an integral membrane protein [PMID:8910473]. Core localization, though less specific than plasma membrane. Supporting Evidence: PMID:8910473 In this study, we report the first measurements of the rate of ATP hydrolysis by purified, reconstituted CFTR |
| GO:1902476 chloride transmembrane transport | IDA PMID:11524016 A monomer is the minimum functional unit required for channe... | ACCEPT | Summary: Direct evidence for CFTR chloride transport from this key study. Reason: This study demonstrated CFTR mediates chloride conduction [PMID:11524016]. Core biological process. Supporting Evidence: PMID:11524016 purified, reconstituted CFTR monomers are sufficient to mediate regulated chloride conduction and ATPase activity |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:11707463 A Golgi-associated PDZ domain protein modulates cystic fibro... | KEEP AS NON CORE | Summary: CFTR transiently localizes to ER membrane during biosynthesis. Reason: CFTR is synthesized and folded in the ER before trafficking to the plasma membrane. ER membrane localization represents a biogenesis intermediate rather than functional localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:11707463 Nov 13. A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. |
| GO:0005886 plasma membrane | IMP PMID:11707463 A Golgi-associated PDZ domain protein modulates cystic fibro... | ACCEPT | Summary: Mutant phenotype evidence for CFTR plasma membrane localization. Reason: CFTR localizes to the plasma membrane [PMID:11524016]. Core localization. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:11707463 Nov 13. A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. |
| GO:1902476 chloride transmembrane transport | IDA PMID:11707463 A Golgi-associated PDZ domain protein modulates cystic fibro... | ACCEPT | Summary: Direct evidence for CFTR chloride transport. Reason: CFTR mediates chloride transmembrane transport [PMID:11524016]. Core biological process. Supporting Evidence: PMID:11524016 The cystic fibrosis transmembrane conductance regulator (CFTR) normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cells PMID:11707463 Nov 13. A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866542 | KEEP AS NON CORE | Summary: CFTR transiently localizes to the ER membrane during biosynthesis before trafficking to the plasma membrane. This Reactome annotation documents CFTR's presence in the ER secretory pathway. Reason: CFTR is synthesized in the ER and must transit through ER quality control before reaching its functional destination at the apical plasma membrane. ER localization represents a transient biosynthetic intermediate rather than CFTR's functional location. The annotation is technically correct but does not represent core function. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866546 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866551 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866553 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866851 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866854 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866856 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866857 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9641109 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9641111 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9641127 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9646348 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9646679 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9646685 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9700266 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway. Reason: CFTR transiently localizes to ER during biosynthesis. This represents trafficking intermediate, not functional localization. Core function is at apical plasma membrane. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866854 | KEEP AS NON CORE | Summary: Reactome annotation indicating CFTR cytosolic domains face the cytosol. The NBD1, NBD2, and R domains of CFTR are cytoplasmic. Reason: CFTR is an integral membrane protein with cytosolic nucleotide-binding and regulatory domains. While cytosol annotation is technically accurate for these domains, CFTR's core localization is the plasma membrane where it functions as a chloride channel. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866858 | KEEP AS NON CORE | Summary: Reactome annotation indicating CFTR cytosolic domains face the cytosol. Reason: CFTR is an integral membrane protein with cytosolic nucleotide-binding and regulatory domains. While technically accurate, CFTR's core localization is the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8866277 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. CFTR functions as a chloride channel at the plasma membrane of epithelial cells. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. This represents CFTR's primary site of action in epithelial cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867754 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867756 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868071 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868072 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868230 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868236 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868648 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868651 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868661 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-6782106 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in endosome membrane during endocytic recycling. CFTR is rapidly endocytosed and recycled back to the plasma membrane. Reason: CFTR transiently localizes to endosomes during its rapid endocytic recycling from the plasma membrane. This is part of CFTR trafficking regulation but not its core functional localization [PMID:19398555]. |
| GO:0005829 cytosol | IDA PMID:24885604 CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exo... | KEEP AS NON CORE | Summary: This study detected CFTR in pancreatic beta-cells using confocal microscopy, showing localization at the plasma membrane with cytosolic domains visible [PMID:24885604]. Reason: CFTR has cytosolic nucleotide-binding and regulatory domains. This study demonstrated CFTR localization in beta-cells but cytosol is not the core functional compartment. Supporting Evidence: PMID:24885604 Localization of CFTR was analyzed as described elsewhere |
| GO:0005886 plasma membrane | IDA PMID:24885604 CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exo... | ACCEPT | Summary: Direct evidence for CFTR plasma membrane localization in pancreatic beta-cells using immunofluorescence microscopy [PMID:24885604]. Reason: This study demonstrated CFTR localization at the plasma membrane of pancreatic beta-cells. Plasma membrane is CFTR's core functional location. Supporting Evidence: PMID:24885604 We detected the presence of CFTR and measured a small CFTR conductance in both human and mouse beta-cells |
| GO:1902476 chloride transmembrane transport | IMP PMID:24885604 CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exo... | ACCEPT | Summary: Direct evidence for CFTR-mediated chloride transport in pancreatic beta-cells. CFTR inhibition reduced cAMP-dependent insulin secretion [PMID:24885604]. Reason: This study demonstrated functional CFTR chloride currents in beta-cells and showed that CFTR inhibitors reduced insulin secretion, confirming CFTR's role in chloride transport. Supporting Evidence: PMID:24885604 The augmentation of insulin secretion at 16.7 mM glucose by activation of CFTR by cAMP (forskolin (FSK) or GLP-1) was significantly inhibited when CFTR antagonists (GlyH-101 and/or CFTRinh-172) were added |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678822 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678992 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5679000 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-5627275 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in lysosomal membrane. Ubiquitinated CFTR that is not recycled is degraded in lysosomes. Reason: CFTR transiently localizes to lysosomes as part of its degradation pathway. This represents protein turnover rather than CFTR's functional localization. |
| GO:0005737 cytoplasm | IDA PMID:18570918 Endosomal SNARE proteins regulate CFTR activity and traffick... | KEEP AS NON CORE | Summary: This study showed CFTR colocalization with endosomal SNARE proteins in Rab11-positive recycling endosomes in the cytoplasm [PMID:18570918]. Reason: CFTR transiently localizes to cytoplasmic compartments during trafficking and recycling. Core localization is at the apical plasma membrane. Supporting Evidence: PMID:18570918 we found a colocalization of CFTR and endosomal SNARE proteins in Rab11-positive recycling endosomes |
| GO:0016324 apical plasma membrane | IDA PMID:18570918 Endosomal SNARE proteins regulate CFTR activity and traffick... | ACCEPT | Summary: This study demonstrated CFTR localization at the apical plasma membrane of epithelial cells and showed that endosomal SNARE overexpression disturbs CFTR apical targeting [PMID:18570918]. Reason: Apical plasma membrane is CFTR's core functional localization in polarized epithelial cells where it mediates chloride and bicarbonate secretion. Supporting Evidence: PMID:18570918 The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein is a chloride channel localized at the apical plasma membrane of epithelial cells |
| GO:0055037 recycling endosome | IDA PMID:18570918 Endosomal SNARE proteins regulate CFTR activity and traffick... | KEEP AS NON CORE | Summary: This study demonstrated CFTR colocalization with endosomal SNARE proteins in Rab11-positive recycling endosomes [PMID:18570918]. Reason: CFTR transiently localizes to recycling endosomes during its endocytic recycling to the plasma membrane. This represents trafficking rather than core functional localization. Supporting Evidence: PMID:18570918 we found a colocalization of CFTR and endosomal SNARE proteins in Rab11-positive recycling endosomes |
| GO:0030660 Golgi-associated vesicle membrane | TAS Reactome:R-HSA-5627071 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in Golgi-associated vesicles during trafficking to the plasma membrane. Reason: CFTR transiently localizes to Golgi-associated vesicles during its biosynthetic trafficking from ER to plasma membrane. This represents trafficking intermediate, not functional localization. |
| GO:0030660 Golgi-associated vesicle membrane | TAS Reactome:R-HSA-5627072 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in Golgi-associated vesicles during trafficking. Reason: CFTR transiently localizes to Golgi-associated vesicles during biosynthetic trafficking. This represents trafficking intermediate, not functional localization. |
| GO:0030660 Golgi-associated vesicle membrane | TAS Reactome:R-HSA-5627275 | KEEP AS NON CORE | Summary: Reactome annotation for CFTR in Golgi-associated vesicles during trafficking. Reason: CFTR transiently localizes to Golgi-associated vesicles during biosynthetic trafficking. This represents trafficking intermediate, not functional localization. |
| GO:0009986 cell surface | IDA PMID:20658517 SLC26A9 stimulates CFTR expression and function in human bro... | ACCEPT | Summary: This study demonstrated CFTR at the cell surface of bronchial epithelial cells and showed SLC26A9 co-expression enhances CFTR surface expression [PMID:20658517]. Reason: Cell surface localization is consistent with CFTR's core function as a chloride channel at the apical plasma membrane of epithelial cells. Supporting Evidence: PMID:20658517 Immunoblots identified a migrating band corresponding to SLC26A9 present in whole-cell lysates as on apical membrane of cells grown on polarized filters |
| GO:0016324 apical plasma membrane | IDA PMID:20658517 SLC26A9 stimulates CFTR expression and function in human bro... | ACCEPT | Summary: This study demonstrated CFTR localization at the apical membrane of polarized bronchial epithelial cells [PMID:20658517]. Reason: Apical plasma membrane is CFTR's core functional localization in polarized epithelial cells. Supporting Evidence: PMID:20658517 Immunoblots identified a migrating band corresponding to SLC26A9 present in whole-cell lysates as on apical membrane of cells grown on polarized filters |
| GO:0015106 bicarbonate transmembrane transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity. CFTR is known to conduct bicarbonate ions in addition to chloride, with approximately 25% permeability relative to chloride [PMID:19019741]. Reason: CFTR bicarbonate conductance is well-established experimentally. Bicarbonate transport is critical for pancreatic and intestinal secretion. |
| GO:0015108 chloride transmembrane transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity. CFTR is well-established as a chloride channel/transporter. Reason: Chloride transport is CFTR's primary molecular function. This annotation correctly captures the core function. |
| GO:0048240 sperm capacitation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation based on sequence similarity. CFTR is expressed in sperm and implicated in capacitation through bicarbonate transport and pH regulation. Reason: Sperm capacitation is a downstream physiological process that depends on CFTR's ion transport activity. While physiologically important for male fertility, this represents a tissue-specific consequence rather than core molecular function. |
| GO:0051454 intracellular pH elevation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation based on sequence similarity. CFTR's bicarbonate conductance can contribute to intracellular pH changes in cells where it is expressed. Reason: Intracellular pH elevation is a downstream consequence of CFTR's bicarbonate transport activity, particularly relevant in sperm capacitation and epithelial secretion. This is physiologically important but not a direct molecular function. |
| GO:0060081 membrane hyperpolarization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation based on sequence similarity. CFTR chloride efflux can contribute to membrane hyperpolarization in sperm and other cells. Reason: Membrane hyperpolarization is a downstream electrophysiological consequence of CFTR's chloride channel activity. This is important for sperm capacitation but represents a secondary effect rather than core molecular function. |
| GO:0071320 cellular response to cAMP | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity. CFTR channel activity is regulated by cAMP-dependent PKA phosphorylation of the R domain. Reason: CFTR is a canonical cAMP-responsive channel. PKA phosphorylation of the R domain is required for channel activation. This accurately reflects CFTR's regulation. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1454916 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-383190 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5627071 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678863 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8866851 | ACCEPT | Summary: Reactome annotation for CFTR plasma membrane localization. Reason: Plasma membrane is CFTR's core functional localization where it conducts chloride and bicarbonate ions. |
| GO:0005886 plasma membrane | IDA PMID:22178883 CFTR and TMEM16A are separate but functionally related Cl- c... | ACCEPT | Summary: This study demonstrated CFTR plasma membrane localization and showed that CFTR and TMEM16A are separate but functionally related chloride channels that can be coimmunoprecipitated [PMID:22178883]. Reason: Plasma membrane is CFTR's core functional localization where it functions as a chloride channel. Supporting Evidence: PMID:22178883 CFTR and TMEM16A were both membrane localized and could be coimmunoprecipitated |
| GO:0019869 chloride channel inhibitor activity | IDA PMID:22178883 CFTR and TMEM16A are separate but functionally related Cl- c... | ACCEPT | Summary: This study showed that activated CFTR inhibits TMEM16A (calcium-activated chloride channel) activity. CFTR activation by IBMX and forskolin completely abrogated TMEM16A-currents [PMID:22178883]. Reason: This annotation captures an important regulatory function of CFTR. CFTR can inhibit TMEM16A/ANO1 calcium-activated chloride channels, representing a channel-channel regulatory interaction. Supporting Evidence: PMID:22178883 TMEM16A-currents were attenuated by additional expression of CFTR, and were completely abrogated when additionally expressed CFTR was activated by IBMX and forskolin |
| GO:0032991 protein-containing complex | IDA PMID:17462998 Myosin Vb is required for trafficking of the cystic fibrosis... | KEEP AS NON CORE | Summary: This study showed that endogenous CFTR formed a complex with myosin Vb and Rab11a in polarized human airway epithelial cells [PMID:17462998]. Reason: CFTR forms complexes with trafficking machinery (myosin Vb, Rab11a) for endocytic recycling. While protein complex formation is important for CFTR regulation, this is a generic term that could be replaced by more specific annotations. Supporting Evidence: PMID:17462998 Endogenous CFTR formed a complex with endogenous myosin Vb and Rab11a |
| GO:0016324 apical plasma membrane | IDA PMID:12801959 Distribution of aquaporin water channels AQP1 and AQP5 in th... | ACCEPT | Summary: This study showed CFTR colocalizes with AQP1 and AQP5 at the apical membrane of intercalated duct cells in human pancreas [PMID:12801959]. Reason: Apical plasma membrane is CFTR's core functional localization in polarized epithelial cells. Supporting Evidence: PMID:12801959 Both AQP1 and AQP5 were colocalised with cystic fibrosis transmembrane conductance regulator (CFTR) at the apical membrane of intercalated duct cells |
| GO:0005769 early endosome | IDA PMID:19398555 The deubiquitinating enzyme USP10 regulates the post-endocyt... | KEEP AS NON CORE | Summary: This study demonstrated that USP10 deubiquitinating enzyme is located in early endosomes and regulates CFTR deubiquitination and trafficking in the post-endocytic compartment [PMID:19398555]. Reason: CFTR transiently localizes to early endosomes during its endocytic recycling pathway. This represents a trafficking compartment rather than core functional localization. Supporting Evidence: PMID:19398555 we demonstrated that Ubiquitin Specific Protease-10 (USP10) is located in early endosomes and regulates the deubiquitination of CFTR and its trafficking in the post-endocytic compartment |
| GO:0019899 enzyme binding | IPI PMID:19398555 The deubiquitinating enzyme USP10 regulates the post-endocyt... | KEEP AS NON CORE | Summary: This study demonstrated CFTR interaction with USP10 deubiquitinating enzyme, which regulates CFTR trafficking by removing ubiquitin to promote recycling [PMID:19398555]. Reason: CFTR binding to USP10 is important for regulating CFTR surface expression through deubiquitination. However, enzyme binding is not CFTR's core molecular function as a chloride channel. Supporting Evidence: PMID:19398555 overexpression of wt-USP10 decreased the amount of ubiquitinated CFTR and increased the abundance of CFTR |
| GO:0005515 protein binding | IPI PMID:9792704 The mechanism underlying cystic fibrosis transmembrane condu... | KEEP AS NON CORE | Summary: This study demonstrated CFTR interaction with Sec61 complex during retrograde translocation from ER to cytosol for proteasomal degradation [PMID:9792704]. Reason: CFTR interaction with Sec61 is part of the ER-associated degradation (ERAD) pathway. While important for understanding CF pathogenesis (especially deltaF508 degradation), protein binding is a generic term and this represents quality control rather than core function. Supporting Evidence: PMID:9792704 During retrograde translocation from the ER to the cytosol, CFTR associates with the Sec61 trimeric complex |
| GO:0016324 apical plasma membrane | IDA PMID:15247260 Myosin VI regulates endocytosis of the cystic fibrosis trans... | ACCEPT | Summary: This study demonstrated endogenous apical membrane CFTR in polarized human airway epithelial cells (Calu-3) and showed myosin VI regulates CFTR endocytosis [PMID:15247260]. Reason: Apical plasma membrane is CFTR's core functional localization in polarized epithelial cells. Supporting Evidence: PMID:15247260 The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-regulated Cl(-) channel expressed in the apical plasma membrane in fluid-transporting epithelia |
| GO:0030165 PDZ domain binding | IDA PMID:11707463 A Golgi-associated PDZ domain protein modulates cystic fibro... | ACCEPT | Summary: This study identified CAL (CFTR associated ligand) as a PDZ domain-containing protein that binds to CFTR C-terminus and modulates its plasma membrane expression [PMID:11707463]. Reason: CFTR's C-terminal PDZ binding motif is critical for interactions with scaffolding proteins like CAL and NHE-RF that regulate CFTR trafficking and surface expression. This is an important regulatory mechanism. Supporting Evidence: PMID:11707463 The PDZ domain of CAL binds to the C terminus of CFTR |
| GO:0005524 ATP binding | TAS PMID:2475911 Identification of the cystic fibrosis gene: cloning and char... | ACCEPT | Summary: The original CFTR cloning paper identified two nucleotide-binding domains (NBDs) with predicted ATP binding properties based on sequence homology to ABC transporters [PMID:2475911]. Reason: ATP binding at NBD1 and NBD2 is essential for CFTR channel gating. This is a core molecular function. Supporting Evidence: PMID:2475911 a domain believed to be involved in ATP (adenosine triphosphate) binding |
| GO:0051453 regulation of intracellular pH | IEA | NEW | Summary: CFTR regulates intracellular and extracellular pH through bicarbonate transport across epithelial membranes Reason: CFTR directly regulates pH homeostasis through its bicarbonate transport function. The channel conducts bicarbonate ions across epithelial cell membranes, which is essential for maintaining proper pH in various secretions including pancreatic juice, airway surface liquid, and reproductive tract fluids. CFTR-mediated bicarbonate transport contributes to both intracellular and extracellular pH regulation, and defects in this function contribute to the pathophysiology of cystic fibrosis. |
| GO:0070254 mucus secretion | IEA | NEW | Summary: CFTR is essential for proper mucus secretion and properties through ion and water transport regulation in secretory epithelia Reason: CFTR plays a critical role in mucus secretion by regulating the ionic composition and hydration of mucus. The channel provides chloride and bicarbonate transport that determines mucus viscosity, pH, and antimicrobial properties. In cystic fibrosis, CFTR dysfunction leads to dehydrated, viscous mucus that cannot be effectively cleared, demonstrating CFTR's essential role in normal mucus secretion and properties. CFTR regulates both the volume and composition of mucus through its ion transport functions. |
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Download this section (compressed HTML)Q: How do different classes of CFTR mutations affect protein folding, trafficking, and channel gating at the molecular level?
Q: What are the regulatory mechanisms that control CFTR channel activity in response to cAMP and other signaling pathways?
Q: How does CFTR dysfunction lead to the characteristic thick mucus secretions and bacterial infections in cystic fibrosis?
Q: What determines tissue-specific sensitivity to CFTR dysfunction and why are some organs more severely affected than others?
Experiment: Single-channel patch-clamp electrophysiology to characterize the gating kinetics and ion selectivity of CFTR variants
Experiment: Cryo-EM structure determination of full-length CFTR in different conformational states and with bound modulators
Experiment: Organoid models of cystic fibrosis using patient-derived cells to test personalized therapeutic approaches
Experiment: Real-time imaging of CFTR trafficking from ER to plasma membrane using fluorescently tagged proteins and live-cell microscopy
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Download this section (compressed HTML)π View Pathway Visualization Interactive pathway diagram with detailed annotations