This entry represents the transmembrane domain in cases where the TMD and ABC region are found in the same protein, and corresponds to ABC type 1 from Transporter Classification Database.
", "llm": false, "checked": false, "updated": false }, { "text": "ABC transporters minimally contain two conserved regions: a highly conserved ATP binding cassette (ABC) and a less conserved transmembrane domain (TMD). In certain bacterial transporters, these regions are found on different polypeptides. The function of the integral inner-membrane protein is to translocate the substrate across the membrane, as well as in substrate recognition [[cite:PUB00014769], [cite:PUB00014770]].
", "llm": false, "checked": false, "updated": false }, { "text": "ABC transporters belong to the ATP-Binding Cassette (ABC) superfamily, which uses the hydrolysis of ATP to energise diverse biological systems. ABC transporters minimally consist of two conserved regions: a highly conserved ATP binding cassette (ABC) and a less conserved transmembrane domain (TMD). These can be found on the same protein or on two different ones. Most ABC transporters function as a dimer and therefore are constituted of four domains, two ABC modules and two TMDs.
\n\nABC transporters are involved in the export or import of a wide variety of substrates ranging from small ions to macromolecules. The major function of ABC import systems is to provide essential nutrients to bacteria. They are found only in prokaryotes and their four constitutive domains are usually encoded by independent polypeptides (two ABC proteins and two TMD proteins). Prokaryotic importers require additional extracytoplasmic binding proteins (one or more per systems) for function. In contrast, export systems are involved in the extrusion of noxious substances, the export of extracellular toxins and the targeting of membrane components. They are found in all living organisms and in general the TMD is fused to the ABC module in a variety of combinations. Some eukaryotic exporters encode the four domains on the same polypeptide chain [[cite:PUB00014769]].
\n\nThe ATP-Binding Cassette (ABC) superfamily forms one of the largest of all protein families with a diversity of physiological functions [[cite:PUB00014769]]. Several studies have shown that there is a correlation between the functional characterisation and the phylogenetic classification of the ABC cassette [[cite:PUB00014769], [cite:PUB00043654]]. More than 50 subfamilies have been described based on a phylogenetic and functional classification [[cite:PUB00014769], [cite:PUB00017894], [cite:PUB00043654]]; (for further information see Transporter Classification Database).
", "llm": false, "checked": false, "updated": false } ], "wikipedia": null, "literature": { "PUB00043654": { "PMID": 11421270, "ISBN": null, "volume": "152", "issue": "3-4", "year": 2001, "title": "The ABC of ABCS: a phylogenetic and functional classification of ABC systems in living organisms.", "URL": null, "raw_pages": "211-29", "medline_journal": "Res Microbiol", "ISO_journal": "Res. Microbiol.", "authors": [ "Dassa E", "Bouige P." ], "DOI_URL": "http://dx.doi.org/10.1016/S0923-2508(01)01194-9" }, "PUB00017894": { "PMID": 11421269, "ISBN": null, "volume": "152", "issue": "3-4", "year": 2001, "title": "ABC transporters: physiology, structure and mechanism--an overview.", "URL": null, "raw_pages": "205-10", "medline_journal": "Res Microbiol", "ISO_journal": "Res. Microbiol.", "authors": [ "Higgins CF." ], "DOI_URL": "http://dx.doi.org/10.1016/S0923-2508(01)01193-7" }, "PUB00014769": { "PMID": 9873074, "ISBN": null, "volume": "48", "issue": "1", "year": 1999, "title": "Getting in or out: early segregation between importers and exporters in the evolution of ATP-binding cassette (ABC) transporters.", "URL": null, "raw_pages": "22-41", "medline_journal": "J Mol Evol", "ISO_journal": "J. Mol. Evol.", "authors": [ "Saurin W", "Hofnung M", "Dassa E." ], "DOI_URL": "http://dx.doi.org/10.1007/PL00006442" }, "PUB00014770": { "PMID": 10529352, "ISBN": null, "volume": "293", "issue": "2", "year": 1999, "title": "ABC-ATPases, adaptable energy generators fuelling transmembrane movement of a variety of molecules in organisms from bacteria to humans.", "URL": null, "raw_pages": "381-99", "medline_journal": "J Mol Biol", "ISO_journal": "J. Mol. Biol.", "authors": [ "Holland IB", "Blight MA." ], "DOI_URL": "http://dx.doi.org/10.1006/jmbi.1999.2993" } }, "set_info": null, "overlaps_with": [ { "accession": "IPR036640", "name": "ABC transporter type 1, transmembrane domain superfamily", "type": "homologous_superfamily" } ], "counters": { "subfamilies": 0, "domain_architectures": 2303, "interactions": 0, "matches": 414210, "pathways": 239, "proteins": 325964, "proteomes": 21798, "sets": 0, "structural_models": { "alphafold": 181002 }, "structures": 626, "taxa": 35650 }, "entry_annotations": { "alignment:seed": 3, "alignment:full": 127 }, "cross_references": { "prositedoc": { "displayName": "PROSITE Doc", "description": "PROSITE is a database of protein families and domains.", "rank": 18, "accessions": [ { "accession": "PDOC00364", "url": "http://prosite.expasy.org/PDOC00364" } ] } }, "is_llm": false, "is_reviewed_llm": false, "is_updated_llm": false, "representative_structure": null } }, "KW-0413.json": { "keyword": { "name": "Isomerase", "id": "KW-0413" }, "definition": "Enzyme that catalyzes the 1,1-, 1,2- or 1,3-hydrogen shift. The 1,1- hydrogen shift is an inversion at an asymmetric carbon center (racemases, epimerases). The 1,2-hydrogen shift involved a hydrogen transfer between two adjacent carbon atoms, one undergoing oxidation, the other reduction (aldose-ketose isomerases). The 1,3-hydrogen shifts are allylic or azaallylic (when nitrogen is one of the three atoms) isomerizations.", "geneOntologies": [ { "goId": "GO:0016853", "name": "isomerase activity" } ], "parents": [ { "keyword": { "name": "Molecular function", "id": "KW-9992" } } ], "category": { "name": "Molecular function", "id": "KW-9992" }, "children": [ { "keyword": { "name": "Rotamase", "id": "KW-0697" } }, { "keyword": { "name": "Topoisomerase", "id": "KW-0799" } } ], "statistics": { "reviewedProteinCount": 17081, "unreviewedProteinCount": 2033034 } } }, "campaign_binding_instruction": { "url": "https://github.com/ai4curation/ai-gene-review/blob/5928e194d4a4e43bdd74b9b1f307a142107daa46/projects/CLINGEN_MENDELIAN.md#L2976-L2978", "path": "projects/CLINGEN_MENDELIAN.md", "sha256": "c0b3ea1e122792dcfbd1bb009cef8a89af52029ddd8ed10fcd7ef670abfc0f53", "scope": "Project-specific user instruction retains supported biologically correct generic binding as non-core unless an evidence-backed refinement is established; unresolved evidence remains UNDECIDED." }, "normal_research_provenance": { "fetch": { "command": [ "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/.venv/bin/python", "-c", "import socket,runpy;socket.setdefaulttimeout(45);runpy.run_module('ai_gene_review.cli',run_name='__main__')", "fetch-gene", "human", "CFTR", "--output-dir", "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/tmp/resume-20261009/CFTR/research-workspace" ], "cwd": "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/tmp/resume-20261009/CFTR/research-workspace", "pid": 34603, "pgid": 34603, "started_at": "2026-10-10T09:42:49.216581+00:00", "bounded_seconds": 1800 }, "publications": { "command": [ "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/.venv/bin/python", "-c", "import socket,runpy;socket.setdefaulttimeout(45);runpy.run_module('ai_gene_review.cli',run_name='__main__')", "fetch-gene-pmids", "human", "CFTR", "--output-dir", "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/tmp/resume-20261009/CFTR/research-workspace/publications" ], "cwd": "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/tmp/resume-20261009/CFTR/research-workspace", "pid": 29439, "pgid": 29439, "started_at": "2026-10-10T09:50:26.690257+00:00", "bounded_seconds": 1800 }, "research": { "command": [ "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/.venv/bin/python", "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/tmp/resume-20261009/CFTR/research-workspace/scripts/deep_research_wrapper.py", "human", "CFTR", "falcon", "--fallback", "perplexity-lite", "--timeout", "90" ], "cwd": "/Users/cjm/orca/workspaces/ai-gene-review/aigr-mendelian/tmp/resume-20261009/CFTR/research-workspace", "pid": 71190, "pgid": 71190, "started_at": "2026-10-10T09:45:50.949666+00:00", "bounded_seconds": 225 }, "provider_report_written": false, "historical_provider_bytes_preserved": true }, "primary_locators": { "19465887": { "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2727442/", "locator": "Original indexed Results, paragraph citing Figure5: USP19 co-IP with GFP-CFTR F508del; no panel pixels claimed" }, "29453757": { "url": "https://link.springer.com/article/10.1007/s10735-018-9759-2", "local_source_sha256": "463d6acabc327128d876dbb3a647a9ce88605ca5bd580dcf87903a91d6a06b9f", "locator": "Selected Methods, Results Figures9–11 and Discussion; actual retrieved URL retained in donor-full-retrieval.json" }, "17085523": { "url": "https://www.researchgate.net/publication/6710662_Altered_cholesterol_homeostasis_in_cultured_and_in_vivo_models_of_cystic_fibrosis", "locator": "Author-uploaded original journal text: selected Methods, Results and Discussion; followup_external_primary_evidence pins the genuine indexed receipts. This updates the earlier abstract-only access boundary." }, "26403673": { "url": "https://pubmed.ncbi.nlm.nih.gov/26403673/", "locator": "Genuine indexed PMC full Methods/Results selected in CFTR-donor-web2.json" }, "21976599": { "url": "https://pubmed.ncbi.nlm.nih.gov/21976599/", "locator": "Authentic abstract plus indexed original Discussion; full method recovery incomplete" } }, "interpretation_boundaries": [ "EC5.6.1.6 is a valid CFTR conformational-ATPase classification; GO0016853 is refined, not declared impossible.", "GO0140359 requires primary active transport; CFTR passive anion flow and ATP gating do not meet it.", "Current official0043225 and0098660 are obsolete; original machine IDs/labels remain exact and replacements have biological reasons.", "Rat nuclear processed-product evidence and human near-basolateral sweat-duct staining are acknowledged without inferring universal intact human localization.", "No CFTR E3 ligase, motor, translocon, kinase or chaperone activity is inferred from substrate/partner recovery.", "The old pathway body and diagram are archived unchanged as historical provenance; the live page now corrects the citations and arrows directly." ], "historical_findings_provenance": { "source_yaml_sha256": "595ab181e0c4692b194a8cddbb8b8d75bfe1fe5d952e3198c58ef9993cbe5118", "scope": "Pre-campaign findings and their original quotations, retained unchanged as historical evidence, not newly authored quotations or an endorsement of every old interpretation. Current assessed findings are in the review YAML.", "records": [ { "reference_id": "GO_REF:0000003", "title": "Gene Ontology annotation based on Enzyme Commission mapping", "findings": [ { "statement": "Automated annotation transfer based on enzyme classification", "supporting_text": "Gene Ontology annotation based on Enzyme Commission mapping" } ] }, { "reference_id": "GO_REF:0000033", "title": "Annotation inferences using phylogenetic trees", "findings": [ { "statement": "Computational inference based on evolutionary conservation across orthologs", "supporting_text": "Annotation inferences using phylogenetic trees" } ] }, { "reference_id": "GO_REF:0000043", "title": "Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping", "findings": [ { "statement": "Automated annotation from Swiss-Prot keywords", "supporting_text": "Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping" } ] }, { "reference_id": "GO_REF:0000107", "title": "Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.", "findings": [ { "statement": "Ortholog-based annotation transfer using Ensembl Compara", "supporting_text": "Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara" } ] }, { "reference_id": "GO_REF:0000120", "title": "Combined Automated Annotation using Multiple IEA Methods.", "findings": [ { "statement": "Combined computational evidence from multiple IEA sources", "supporting_text": "Combined Automated Annotation using Multiple IEA Methods" } ] }, { "reference_id": "PMID:12471024", "title": "The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins.", "findings": [ { "statement": "ClC-3B chloride channel localizes to Golgi and interacts with CFTR-associated PDZ proteins", "supporting_text": "ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins" } ] }, { "reference_id": "PMID:16546175", "title": "Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat.", "findings": [ { "statement": "Miglustat rescues functional ΔF508-CFTR channels in CF epithelial cells", "supporting_text": "Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat" } ] }, { "reference_id": "PMID:17110338", "title": "Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.", "findings": [ { "statement": "Hsp90 cochaperones modulate CFTR protein folding and ΔF508 can be rescued by reducing Aha1", "supporting_text": "Cell-surface rescue of the most common disease variant that is restricted to the ER, DeltaF508, can be initiated by partial siRNA silencing of the Hsp90 cochaperone ATPase regulator Aha1" }, { "statement": "CFTR interactome reveals chaperone network controlling protein folding for ER exit", "supporting_text": "Using proteomics to assess global cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein interactions (the CFTR interactome), we show that Hsp90 cochaperones modulate Hsp90-dependent stability of CFTR protein folding" } ] }, { "reference_id": "PMID:8910473", "title": "ATPase activity of the cystic fibrosis transmembrane conductance regulator.", "findings": [ { "statement": "First direct measurement of ATP hydrolysis rate by purified CFTR demonstrating intrinsic ATPase activity", "supporting_text": "In this study, we report the first measurements of the rate of ATP hydrolysis by purified, reconstituted CFTR" }, { "statement": "G551D mutation causes defective ATP hydrolysis and channel gating, proving ATP utilization for channel activity", "supporting_text": "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" } ] }, { "reference_id": "PMID:9931011", "title": "Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator).", "findings": [ { "statement": "Walker A and B mutations in NBDs affect ATP hydrolysis and channel gating differentially", "supporting_text": "Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR" } ] } ] }, "followup_external_primary_evidence": [ { "pmid": "29453757", "url": "https://link.springer.com/article/10.1007/s10735-018-9759-2", "receipt_path": "tmp/resume-20261009/CFTR/manual-evidence/29453757-external.html", "receipt_sha256": "463d6acabc327128d876dbb3a647a9ce88605ca5bd580dcf87903a91d6a06b9f", "locator": "Results, CFTR localization in Sertoli cells; Figures 9–11; biochemical fractionation and Western blot Methods.", "facts_paraphrase": "Rat tissue, antigen competition and a second antiserum support nuclear immunoreactivity; the nuclear band is approximately 85 kDa, not identified as intact human CFTR.", "external_excerpt": "the nuclear fraction showed a very strong band", "excerpt_kind": "Verbatim external primary text" }, { "pmid": "26403673", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC4681480/", "receipt_path": "tmp/resume-20261009/CFTR/manual-evidence/CFTR-donor-web2.json", "receipt_sha256": "d5ee700dfe46a082ffab94aacbf8e30210970014c3077dc444459d86861e209b", "locator": "Original article only: Methods lines 122–136, Results from line 137; continued selected text in CFTR-donor-web3.json.", "facts_paraphrase": "Mouse knockout/fluoride comparisons and enamel elemental assays; the antibody localization panels concern Nckx4/NaPi-2b, not CFTR.", "external_excerpt": "", "excerpt_kind": "No new primary quotation" }, { "pmid": "19019741", "url": "https://www.sciencedirect.com/science/article/pii/S1569199308001495", "receipt_path": "tmp/resume-20261009/CFTR-root-core-peer/web-3.json", "receipt_sha256": "1526aea746946695ea1a632a0c3103eacafcbd1c527392ec75c6ac6e79752724", "locator": "Original article titled Mechanism of direct bicarbonate transport by the CFTR anion channel; Methods section 2, Results 3.1, Discussion 4.", "facts_paraphrase": "Human CFTR expressed in BHK cells; activated excised patches measure bicarbonate currents under high substrate conditions. The existing short YAML/notes quotes remain the source anchors.", "external_excerpt": "", "excerpt_kind": "No new primary quotation" }, { "pmid": "17085523", "url": "https://www.researchgate.net/publication/6710662_Altered_cholesterol_homeostasis_in_cultured_and_in_vivo_models_of_cystic_fibrosis", "receipt_path": "tmp/resume-20261009/CFTR-followup-4568/cftr_cholesterol_results.json", "receipt_sha256": "241e45cc5fba89ab3a20a16a38709d44f286c405e803a5c1c22128baadf8642d", "locator": "Original journal author copy: Methods (cell models and synthesis), Results (distribution, GC-MS synthesis), Discussion (WT rescue and unresolved mechanism).", "facts_paraphrase": "The preserved human TSV and mouse donor both assert acts_upstream_of_or_within.", "external_excerpt": "", "excerpt_kind": "No new primary quotation" } ], "followup_schema_access_decision": { "schema": "full_text_unavailable is optional and describes availability; the validator uses it as a fallback for uncached quotations.", "decision": "Omit the ambiguous optional flag for the four externally inspected sources, preserve exact machine caches, state canonical cache status and actual external reading separately, and use supporting_text_fulltext for the external-only anchor.", "no_full_cache_replacement": true }, "followup_cholesterol_source": { "official_terms": { "0006695": { "url": "https://www.ebi.ac.uk/QuickGO/services/ontology/go/terms/GO%3A0006695", "status": 200, "response": { "numberOfHits": 1, "results": [ { "id": "GO:0006695", "isObsolete": false, "name": "cholesterol biosynthetic process", "definition": { "text": "The chemical reactions and pathways resulting in the formation of cholesterol, cholest-5-en-3 beta-ol, the principal sterol of vertebrates and the precursor of many steroids, including bile acids and steroid hormones." }, "synonyms": [ { "name": "cholesterol anabolism", "type": "exact" }, { "name": "cholesterol biosynthesis", "type": "exact" }, { "name": "cholesterol formation", "type": "exact" }, { "name": "cholesterol synthesis", "type": "exact" } ], "children": [ { "id": "GO:0045540", "relation": "regulates" }, { "id": "GO:0045542", "relation": "positively_regulates" }, { "id": "GO:0045541", "relation": "negatively_regulates" } ], "aspect": "biological_process", "usage": "Unrestricted" } ], "pageInfo": null } }, "0030301": { "url": "https://www.ebi.ac.uk/QuickGO/services/ontology/go/terms/GO%3A0030301", "status": 200, "response": { "numberOfHits": 1, "results": [ { "id": "GO:0030301", "isObsolete": false, "name": "cholesterol transport", "definition": { "text": "The directed movement of cholesterol, cholest-5-en-3-beta-ol, into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore.", "xrefs": [ { "dbCode": "ISBN", "dbId": "0198506732" } ] }, "children": [ { "id": "GO:0043691", "relation": "is_a" }, { "id": "GO:0010879", "relation": "is_a" }, { "id": "GO:0032374", "relation": "regulates" }, { "id": "GO:0070508", "relation": "is_a" }, { "id": "GO:0032376", "relation": "positively_regulates" }, { "id": "GO:0032367", "relation": "is_a" }, { "id": "GO:0032375", "relation": "negatively_regulates" }, { "id": "GO:0033344", "relation": "is_a" } ], "aspect": "biological_process", "usage": "Unrestricted" } ], "pageInfo": null } }, "0051649": { "url": "https://www.ebi.ac.uk/QuickGO/services/ontology/go/terms/GO%3A0051649", "status": 200, "response": { "numberOfHits": 1, "results": [ { "id": "GO:0051649", "isObsolete": false, "name": "establishment of localization in cell", "definition": { "text": "Any process, occurring in a cell, that localizes a substance or cellular component. 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CFTR conducts chloride and bicarbonate passively through an ATP-regulated pore; ATP hydrolysis controls conformation rather than pumping ions uphill. Direct bicarbonate permeation and stable tested selectivity are supported by PMID:19019741; the dynamic external-chloride model belongs to PMID:15010471.\n\nPMID:12369822 supports CFTR binding to NHERF2/E3KARP as a comparator in a DRA-focused study; it does not make DRA the original CFTR binding partner. ClC-3B/PDZ-organized association in PMID:12471024 does not independently establish that ClC-3B controls CFTR trafficking. PMID:19289574 supports SLC26A9 association/functional coupling, not ENaC regulation. Human airway rescue in PMID:19621064 measures sodium transport as well as fluid/chloride endpoints; an inferred CFTR effect on ENaC would run from CFTR to sodium-channel behavior, not the historical diagram's reverse inhibitory arrow. A direct molecular CFTR-to-ENaC step remains unresolved, so the current core does not assert one. Mucus hydration and clearance are distinguished from regulated mucus secretion.\n\nThe historical drug discussion is a dated narrative, not a current clinical recommendation. See [the current review](CFTR-ai-review.yaml), [appended audit notes](CFTR-notes.md) and [literal source evidence](CFTR-source-evidence.json) for the current bounded conclusions.\n\n---\n\n## Preserved historical pathway narrative and superseded diagram\n\n# Pathway Summary for CFTR\n\n## Overview\nCFTR (Cystic Fibrosis Transmembrane Conductance Regulator) is a unique ABC transporter that functions as a phosphorylation- and ATP-regulated anion channel rather than an active pump. It conducts chloride and bicarbonate ions across epithelial cell apical membranes, playing critical roles in fluid secretion, mucociliary clearance, and salt balance [PMID:11524016]. Channel activation requires PKA phosphorylation of the regulatory R domain and ATP binding/hydrolysis at nucleotide-binding domains, integrating cAMP signaling with epithelial ion transport.\n\n## Core Signaling Pathways\n\n### cAMP-PKA Signaling Pathway\nCFTR activation is primarily controlled by the cAMP-PKA pathway. Hormones and neurotransmitters activate adenylyl cyclase, elevating cAMP levels which activate PKA. PKA phosphorylates multiple serine residues in CFTR's R domain, priming the channel for ATP-dependent gating [PMID:11524016]. This pathway is essential for regulated fluid secretion in airways, intestines, and exocrine glands.\n\n### ATP-Dependent Channel Gating\nCFTR channel gating requires ATP binding and hydrolysis at its two nucleotide-binding domains (NBD1 and NBD2). ATP binding promotes NBD dimerization triggering channel opening, while ATP hydrolysis at NBD2 drives channel closure [PMID:8910473]. This creates a gating cycle where the channel alternates between open and closed states in an ATP-dependent manner.\n\n### Epithelial Ion Transport Network\nCFTR functions within a coordinated network of epithelial ion transporters. It functionally couples with SLC26 anion exchangers (particularly DRA/SLC26A3) for chloride/bicarbonate exchange [PMID:12369822], and negatively regulates ENaC sodium channels to maintain proper ion and fluid balance across epithelia [PMID:15010471].\n\n## Pathway Diagram\n\n```mermaid\ngraph TD\n A[GPCR: Hormone/Neurotransmitter Receptor] --> B[Adenylyl Cyclase: cAMP Synthesis]\n B --> C[cAMP: Second Messenger]\n C --> D[PKA: Protein Kinase A]\n D -->|phosphorylates R domain| E[\"CFTR: Anion Channel (Apical Membrane)\"]\n \n F[ATP: Energy Source] --> G[NBD1/NBD2: Nucleotide Binding Domains]\n G -->|ATP binding/hydrolysis| E\n \n E -->|Cl- secretion| H[Lumen: Fluid Secretion]\n E -->|HCO3- secretion| H\n \n I[DRA/SLC26A3: Cl-/HCO3- Exchanger] <-.->|functional coupling| E\n J[ENaC: Na+ Channel] -.->|inhibits| E\n \n K[Shank2: PDZ Scaffold] -.->|negative regulation| E\n L[ClC-3B: Chloride Channel] -.->|trafficking regulation| E\n \n M[Hsp90/Aha1: Chaperone Complex] -.->|folding/quality control| E\n N[ERAD: Degradation Pathway] -.->|misfolded CFTR| E\n \n style E fill:#f9f,stroke:#333,stroke-width:2px\n style D fill:#ffd,stroke:#333,stroke-width:1px\n style G fill:#dfd,stroke:#333,stroke-width:1px\n```\n\n## Upstream Regulators\n- **Hormonal signals**: VIP, secretin, prostaglandins activate adenylyl cyclase [PMID:11524016]\n- **cAMP-PKA cascade**: PKA phosphorylation of R domain serine residues enables channel activation\n- **ATP availability**: Intracellular ATP levels control channel gating frequency [PMID:8910473]\n\n## Downstream Effects\n- **Chloride secretion**: Primary anion conducted, drives transepithelial fluid secretion [PMID:11524016]\n- **Bicarbonate secretion**: Important for pH regulation and mucin hydration [PMID:15010471]\n- **ENaC inhibition**: Reduces sodium absorption to maintain ion balance\n- **Fluid secretion**: Controls hydration of airway surface liquid, digestive secretions, and sweat\n\n## Protein Interactions and Regulation\n- **DRA/SLC26A3**: Functional coupling for coordinated Cl-/HCO3- exchange [PMID:12369822]\n- **Shank2**: PDZ-domain scaffold that negatively regulates CFTR activity [PMID:14679199]\n- **ClC-3B**: Golgi-localized chloride channel involved in CFTR trafficking [PMID:12471024]\n- **Quality control machinery**: Hsp90/Aha1 chaperones and ERAD components process misfolded CFTR [PMID:16901789, PMID:17110338]\n\n## Disease Pathways\n\n### Cystic Fibrosis Pathogenesis\nLoss-of-function mutations cause cystic fibrosis through multiple mechanisms:\n- **ΔF508 mutation**: Protein misfolding and ER retention, most common CF mutation [PMID:16546175]\n- **Defective chloride secretion**: Leads to thick, dehydrated mucus in airways\n- **Pancreatic insufficiency**: Loss of digestive enzyme secretion\n- **Male infertility**: Congenital bilateral absence of vas deferens\n\n### Secretory Diarrhea\nCFTR hyperactivation by bacterial toxins (e.g., cholera toxin) causes excessive fluid secretion. Lysophosphatidic acid can inhibit CFTR-mediated secretory diarrhea through protein interactions [PMID:16203867].\n\n## Therapeutic Targets\n- **CFTR modulators**: Potentiators enhance channel gating, correctors improve folding/trafficking\n- **Chaperone modulation**: Targeting Hsp90/Aha1 to rescue misfolded CFTR [PMID:17110338]\n- **Miglustat**: Alpha-glucosidase inhibitor that rescues ΔF508-CFTR function [PMID:16546175]\n\n## Tissue-Specific Functions\n- **Airways**: Mucociliary clearance through airway surface liquid hydration\n- **Intestine**: Fluid secretion and pH regulation via HCO3- transport\n- **Pancreas**: Digestive enzyme secretion and ductal fluid flow\n- **Sweat glands**: Salt reabsorption (defective in CF leading to high sweat chloride)\n\n## Integration with Cellular Processes\nCFTR integrates multiple cellular signals:\n1. **Hormonal regulation**: Responds to systemic signals via cAMP\n2. **Metabolic state**: ATP-dependent gating links to cellular energy status\n3. **Ion homeostasis**: Coordinates with other channels/transporters for epithelial ion balance\n4. **Quality control**: Subject to extensive ER quality control and ERAD pathways", "disposition": "Corrected live assertions/diagram; prior version retained here as historical provenance, not current biology." }, "followup_review": { "head": "d7b5f12fe6c34a88edd438a540464d0b305b3fb3", "review": 5478806522, "comment": 6097036592, "policy": "The 25-word aggregate source quote budget is an authoring constraint, not a repository validator rule. 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Retain the independently supported CFTR location and original citation.", "new_words": 0 }, { "incoming_index": 92, "path": "$.existing_annotations[193].review.supported_by[0].supporting_text", "reference": "PMID:22178883", "disposition": "RETAIN", "reason": "Abstract: membrane localization and co-immunoprecipitation, not shared channel identity.", "new_words": 11 }, { "incoming_index": 93, "path": "$.existing_annotations[194].review.supported_by[0].supporting_text", "reference": "PMID:22178883", "disposition": "REPLACE_WITH_SHORT_TARGET_EXCERPT", "reason": "Abstract: TMEM16A-current attenuation after CFTR coexpression, not a general channel-inhibitor mechanism.", "new_words": 9 }, { "incoming_index": 94, "path": "$.existing_annotations[195].review.supported_by[0].supporting_text", "reference": "PMID:17462998", "disposition": "RETAIN", "reason": "Abstract: endogenous CFTR/myosinVb/Rab11a complex in polarized human airway cells.", "new_words": 11 }, { "incoming_index": 95, "path": "$.existing_annotations[196].review.supported_by[0].supporting_text", "reference": "PMID:12801959", "disposition": "RETAIN", "reason": "Abstract Results: human pancreatic intercalated-duct apical CFTR colocalization.", "new_words": 21 }, { "incoming_index": 96, "path": "$.existing_annotations[197].review.supported_by[0].supporting_text", "reference": "PMID:19398555", "disposition": "REMOVE_ADDED_EXCERPT", "reason": "The added sentence explicitly locates USP10, not CFTR; it does not anchor the CFTR early-endosome assertion.", "new_words": 0 }, { "incoming_index": 97, "path": "$.existing_annotations[198].review.supported_by[0].supporting_text", "reference": "PMID:19398555", "disposition": "REMOVE_ADDED_EXCERPT", "reason": "The added abundance/ubiquitination result does not itself demonstrate the asserted enzyme association; original source-specific evidence remains.", "new_words": 0 }, { "incoming_index": 98, "path": "$.existing_annotations[200].review.supported_by[0].supporting_text", "reference": "PMID:15247260", "disposition": "REMOVE_ADDED_EXCERPT", "reason": "Avoid repeated or over-budget excerpts; retained earlier short source-specific anchors and evidence paragraphs already cover this claim.", "new_words": 0 }, { "incoming_index": 99, "path": "$.existing_annotations[201].review.supported_by[0].supporting_text", "reference": "PMID:11707463", "disposition": "RETAIN", "reason": "Abstract: CAL PDZ domain binds the CFTR C terminus; repeat counted in source total.", "new_words": 12 }, { "incoming_index": 100, "path": "$.existing_annotations[202].review.supported_by[0].supporting_text", "reference": "PMID:2475911", "disposition": "REMOVE_ADDED_EXCERPT", "reason": "A methods cross-reference or historical predicted-domain sentence does not independently anchor the asserted measured target function/location.", "new_words": 0 }, { "incoming_index": 101, "path": "$.core_functions[0].supported_by[1].supporting_text", "reference": "PMID:19621064", "disposition": "REPLACE_WITH_SHORT_TARGET_EXCERPT", "reason": "Abstract: CFTR delivery restores airway-surface-liquid regulation and mucus transport; no direct mucus-transporter MF.", "new_words": 7 }, { "incoming_index": 102, "path": "$.core_functions[1].supported_by[1].supporting_text", "reference": "PMID:15010471", "disposition": "REMOVE_ADDED_EXCERPT", "reason": "The added text is a title/date or broad topic label rather than an exact target-assay anchor; preserve the original reference and substantive source-evidence paragraph without presenting metadata as assay evidence.", "new_words": 0 }, { "incoming_index": 103, "path": "$.core_functions[2].supported_by[2].supporting_text", "reference": "PMID:10581360", "disposition": "REMOVE_ADDED_EXCERPT", "reason": "The added text is a title/date or broad topic label rather than an exact target-assay anchor; preserve the original reference and substantive source-evidence paragraph without presenting metadata as assay evidence.", "new_words": 0 } ], "primary_excerpt_storage": "Actual short excerpts occur only in YAML; this ledger gives assay-scope paraphrases, not duplicate literature quotes. Existing external excerpts and inherited provenance remain unchanged." }, "evidence_link_followup_4568": { "source_head": "69a260f8bdef0e0cdd5bc83a9a545f8775110a7a", "removed_authored_self_quotations": 35, "citation_scope": "Bare file references retain access to literal source records and explicitly authored interpretations; adjacent primary quotations are unchanged.", "qualifier_backfill": [ { "index": 26, "qualifier": "acts_upstream_of_or_within", "line": 303, "record": { "GENE PRODUCT DB": "UniProtKB", "GENE PRODUCT ID": "P13569", "SYMBOL": "CFTR", "QUALIFIER": "acts_upstream_of_or_within", "GO TERM": "GO:0006695", "GO NAME": "cholesterol biosynthetic process", "GO ASPECT": "biological_process", "ECO ID": "ECO:0000265", "GO EVIDENCE CODE": "IEA", "REFERENCE": "GO_REF:0000107", "WITH/FROM": "UniProtKB:P26361|ensembl:ENSMUSP00000049228", "TAXON ID": "9606", "TAXON NAME": "Homo sapiens", "ASSIGNED BY": "Ensembl", "GENE NAME": "Cystic fibrosis transmembrane conductance regulator", "DATE": "20250527" }, "current_reason": "The preserved GOA qualifier is acts_upstream_of_or_within, also present on the mouse IMP donor. PMID:17085523 measures increased synthesis by deuterium incorporation/GC-MS after Cftr loss. This supports the broad upstream assertion, without assigning CFTR a sterol-synthetic reaction. The qualifier field now records the relationship already present in the preserved GOA." }, { "index": 27, "qualifier": "acts_upstream_of_or_within", "line": 306, "record": { "GENE PRODUCT DB": "UniProtKB", "GENE PRODUCT ID": "P13569", "SYMBOL": "CFTR", "QUALIFIER": "acts_upstream_of_or_within", "GO TERM": "GO:0030301", "GO NAME": "cholesterol transport", "GO ASPECT": "biological_process", "ECO ID": "ECO:0000265", "GO EVIDENCE CODE": "IEA", "REFERENCE": "GO_REF:0000107", "WITH/FROM": "UniProtKB:P26361|ensembl:ENSMUSP00000049228", "TAXON ID": "9606", "TAXON NAME": "Homo sapiens", "ASSIGNED BY": "Ensembl", "GENE NAME": "Cystic fibrosis transmembrane conductance regulator", "DATE": "20250527" }, "current_reason": "The preserved GOA and mouse donor use acts_upstream_of_or_within. PMID:17085523 reports abnormal cholesterol distribution and correction in cells expressing full-length wild-type CFTR. Retain that causal upstream scope; the molecular transport mechanism remains unresolved, and this is not evidence that CFTR translocates cholesterol through its pore. The qualifier field now records the relationship already present in the preserved GOA." }, { "index": 28, "qualifier": "acts_upstream_of_or_within", "line": 309, "record": { "GENE PRODUCT DB": "UniProtKB", "GENE PRODUCT ID": "P13569", "SYMBOL": "CFTR", "QUALIFIER": "acts_upstream_of_or_within", "GO TERM": "GO:0051649", "GO NAME": "establishment of localization in cell", "GO ASPECT": "biological_process", "ECO ID": "ECO:0000265", "GO EVIDENCE CODE": "IEA", "REFERENCE": "GO_REF:0000107", "WITH/FROM": "UniProtKB:P26361|ensembl:ENSMUSP00000049228", "TAXON ID": "9606", "TAXON NAME": "Homo sapiens", "ASSIGNED BY": "Ensembl", "GENE NAME": "Cystic fibrosis transmembrane conductance regulator", "DATE": "20250527" }, "current_reason": "The original GOA qualifier is acts_upstream_of_or_within. Its historical Ensembl mapping to this broad localization term has not been reconstructed from the current mouse records. The cholesterol findings support upstream homeostasis but do not identify which localization assertion generated this transfer. Preserve the source while leaving that specific mapping unresolved; uncertainty is not limited to inaccessible publications. The qualifier field now records the relationship already present in the preserved GOA." } ], "preservation": "Every previously populated source field, action, product, reference identity, primary excerpt, underlying source cache and previous artifact field remains unchanged. Three previously absent qualifiers are populated from the preserved GOA. Existing artifact snapshots retain their historical serialization." } }