{"gene":"COL17A1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1991,"finding":"BP180/COL17A1 contains two collagen triple-helical domains (242 and 30 amino acids) separated by a non-collagen stretch; collagenase digestion of the encoded fusion protein generated a peptide fragment consistent with predicted cleavage sites, establishing the collagenous nature of these domains.","method":"cDNA sequence analysis, collagenase digestion of recombinant fusion protein","journal":"The Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay confirming collagenous domain identity, single lab, single study","pmids":["1846881"],"is_preprint":false},{"year":1992,"finding":"BP180/COL17A1 is a type II transmembrane protein with an intracellular N-terminus and a long C-terminal extracellular collagenous domain consisting of 15 collagen domains separated by non-collagenous sequences; a transmembrane domain located 76 amino acids upstream of the collagenous region acts as a signal-anchor directing the C-terminal collagenous segment to the cell exterior.","method":"cDNA cloning and primary structural analysis, open reading frame prediction","journal":"The Journal of Investigative Dermatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — complete structural prediction confirmed by multiple subsequent experimental studies and disease mutations; independently replicated","pmids":["1324962"],"is_preprint":false},{"year":1993,"finding":"BP180/BPAG2 autoantibody-reactive region (NC16A, non-collagenous domain) is localized extracellularly to the epidermal basal lamina immediately adjacent to the hemidesmosome, confirming type II transmembrane orientation with the C-terminal collagenous domain projecting into the basal lamina.","method":"Bacterial fusion protein expression, immunoblotting, immunoadsorption, immunofluorescence with affinity-purified antiserum","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunoadsorption and localization with affinity-purified antibody, replicated across multiple disease sera and subsequent studies","pmids":["8228259"],"is_preprint":false},{"year":1997,"finding":"The BP180 ectodomain exists as an elongated, flexible homotrimeric structure; a recombinant secreted form (sec180e) assembles as a stable homotrimer prior to secretion, with a Stokes radius of 13.6 nm, sedimentation coefficient of 6.5 S, and frictional ratio of 3.01, indicating highly extended conformation; native BP180 from human epidermis also exists in a heat-labile, SDS-stable high-molecular-mass complex.","method":"Gel filtration, sedimentation analysis, pulse-chase, chemical cross-linking, COS-1 cell expression","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biophysical methods (gel filtration, sedimentation, cross-linking) in a single rigorous study confirming homotrimeric assembly","pmids":["9220968"],"is_preprint":false},{"year":1995,"finding":"BP180/COL17A1 cytoplasmic domain interacts with the alpha6 integrin subunit; a deletion mutant lacking the extracellular collagenous domains (D1) co-precipitates with alpha6 integrin in HT1080 transfectants, and a 36-amino-acid N-terminal cytoplasmic deletion (D1-36N) disrupts polarization, while deletion of the 27-aa non-collagenous extracellular juxtamembrane domain (D1-27C) prevents co-distribution with hemidesmosomal components.","method":"Transfection of deletion mutants into 804G, FG, and HT1080 cells; co-immunoprecipitation; immunofluorescence localization","journal":"The Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation and systematic deletion mutagenesis in multiple cell lines, single lab","pmids":["7790367"],"is_preprint":false},{"year":1998,"finding":"BP180 interacts with alpha6 integrin via the non-collagenous NC16A extracellular domain (residues 506-519); this interaction is necessary for hemidesmosome assembly, as a 14-mer peptide spanning this region inhibits the BP180/alpha6 interaction in yeast two-hybrid and recombinant assays and blocks hemidesmosome assembly in 804G cells.","method":"Yeast two-hybrid, recombinant protein interaction assay, peptide inhibition, cell culture hemidesmosome assembly assay","journal":"The Journal of Investigative Dermatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted interaction with mutagenesis-equivalent peptide inhibition plus cell-based functional assay, multiple orthogonal approaches, single lab","pmids":["9856810"],"is_preprint":false},{"year":1998,"finding":"The intracellular domain of BP180 (amino acids 13–89, including a predicted N-terminal beta-sheet) directly interacts with the beta4 integrin subunit intracellular domain (requiring the connecting segment, second pair of FNIII repeats, and tail region of beta4) as established by yeast two-hybrid analysis.","method":"Yeast two-hybrid system with serial deletion constructs","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP equivalent (yeast two-hybrid), single lab, single method","pmids":["9500991"],"is_preprint":false},{"year":1997,"finding":"BP180 cytoplasmic domain contains sufficient information for recruitment into hemidesmosomes; a 265-amino-acid segment spanning the central and N-terminal portions of the cytoplasmic domain mediates hemidesmosomal localization; co-localization with alpha6beta4 requires sequences within the cytoplasmic tail of beta4 (specifically the C-terminal half and the tyrosine activation motif).","method":"Transfection of wild-type and deletion mutant cDNA constructs into 804G and COS-7 cells; immunofluorescence localization","journal":"The Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic deletion mutagenesis with cell localization readout, multiple constructs, single lab","pmids":["9087447"],"is_preprint":false},{"year":2000,"finding":"The N-terminal domain of BP180 directly binds the N-terminal domain of BP230; expression of the BP230 N-terminus in 804G cells disrupts BP180 distribution at hemidesmosome sites, competing with endogenous BP230 for BP180 binding, thereby demonstrating that this interaction is required for BP180 incorporation into the hemidesmosome.","method":"Yeast two-hybrid, recombinant protein binding, cell transfection with dominant-negative fragment","journal":"Molecular Biology of the Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus recombinant protein interaction plus dominant-negative cell transfection, single lab, multiple orthogonal approaches","pmids":["10637308"],"is_preprint":false},{"year":2003,"finding":"BP180 binds both BP230 and plectin via the Y subdomain of their N-terminal plakin domains interacting with residues 145–230 of the BP180 cytoplasmic domain; different but overlapping sequences on BP180 mediate binding to beta4 integrin (which associates via its third FNIII repeat); BP230 localization into hemidesmosome-like structures depends on its Z-Y subdomains and requires available BP180.","method":"Yeast two-hybrid, cell transfection assays, domain mapping","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain mapping by yeast two-hybrid and cell-transfection, single lab, multiple interaction partners mapped","pmids":["12482924"],"is_preprint":false},{"year":1998,"finding":"BP180 is constitutively cleaved on the cell surface to release a 120-kDa collagenous extracellular fragment (LAD-1); the cleavage product lacks the globular head present in intact BP180 and is detectable in culture medium and in vivo in bovine skin basement membrane; it is recognized by a monoclonal antibody (1337) that binds an epitope exposed only upon cleavage.","method":"Immunofluorescence microscopy, immunoprecipitation, rotary shadow electron microscopy, immunoblotting","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical purification, electron microscopy, and cell-based secretion assay demonstrating constitutive ectodomain cleavage in vitro and in vivo","pmids":["9545306"],"is_preprint":false},{"year":1997,"finding":"The BP180 extracellular domain projects through the lamina lucida to the lamina densa; immuno-electron microscopy with antibodies to the NC16A (membrane-proximal) domain localizes to the upper lamina lucida, whereas antibodies to the C-terminal region localize to the lower lamina lucida/lamina densa interface, co-localizing with anchoring filaments and laminin-5.","method":"Immunoelectron microscopy, immunogold localization, immunoadsorption","journal":"The Journal of Investigative Dermatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct ultrastructural localization of distinct BP180 domains using multiple antibodies, replicated across multiple patient sera and rabbit antisera","pmids":["9182819"],"is_preprint":false},{"year":1997,"finding":"The C-terminus (distal ectodomain) of BPAG2/COL17A1 localizes within the lamina densa, 41 nm beneath the plasma membrane of basal keratinocytes, and the extracellular domain runs along anchoring filaments; this was established using anti-BV4 IgG raised against a baculovirus-expressed C-terminal recombinant of BPAG2.","method":"Baculovirus expression, affinity purification, immunogold electron microscopy (pre- and post-embedding)","journal":"The Journal of Investigative Dermatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct immunogold EM with pre- and post-embedding methods quantifying position of C-terminus in tissue","pmids":["9242508"],"is_preprint":false},{"year":2000,"finding":"In vivo, the extracellular domain of BPAG2 has at least one loop structure in the lamina densa; immunogold EM with antibodies to intracellular head (20 nm from membrane), mid-extracellular portion (~amino acids 1000–1320, 65 nm from membrane), and C-terminal end (~amino acids 1320–1500, 39 nm from membrane) demonstrates that the C-terminal end is closer to the plasma membrane than the mid-extracellular region, implying a loop.","method":"Low temperature post-embedding immunoelectron microscopy with three domain-specific monoclonal antibodies","journal":"The Journal of Investigative Dermatology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous immunogold EM method but single lab, single study","pmids":["11069628"],"is_preprint":false},{"year":2001,"finding":"Neutrophil elastase (NE) directly cleaves the extracellular collagenous domain of BP180 in human bullous pemphigoid lesions and blister fluid; NE but not proMMP-9 (which remains inactive in blister fluid, where TIMP-1 levels are high) is responsible for direct BP180 proteolysis during blister formation.","method":"In vitro proteolysis of recombinant BP180 with recombinant MMP-9, NE, and blister fluid; inhibition with chloromethylketone (elastase inhibitor) or batimastat (MMP inhibitor); lesional skin and blister fluid analysis","journal":"The Journal of Investigative Dermatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro proteolysis with specific inhibitors, biological fluids, multiple patient samples","pmids":["11710917"],"is_preprint":false},{"year":2004,"finding":"Shedding of collagen XVII/BP180 ectodomain requires the conformational integrity of the NC16A linker domain; the stretch of amino acids 528–547 within NC16A is critical for sheddase recognition and cleavage; furin does not directly cleave collagen XVII but activates ADAMs; large NC16A deletions preventing shedding also result in lower triple-helix thermal stability.","method":"Deletion mutagenesis of NC16A domain, expression in COS-7 cells, shedding assay, secondary structure prediction, triple-helix folding thermal stability assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic deletion mutagenesis with shedding assay and structural analysis, multiple orthogonal methods, single lab","pmids":["15047704"],"is_preprint":false},{"year":2009,"finding":"ADAM10 and ADAM9 are the major sheddases for collagen XVII/BP180 in primary keratinocytes; constitutive shedding is strongly reduced in Adam10−/− cells and is sensitive to the ADAM10-selective inhibitor GI254023X; Adam9−/− keratinocytes show 55% reduction in constitutive shedding; H2O2 enhances ADAM9 expression and stimulates collagen XVII shedding, an effect absent in Adam9−/− mice; ADAM17 only indirectly affects collagen XVII shedding (phorbol ester stimulation does not increase shedding).","method":"Adam10−/− and Adam9−/− knockout keratinocytes, selective ADAM inhibitor GI254023X, H2O2 stimulation, in vivo mouse skin experiments","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with selective inhibitor and in vivo experiments, multiple orthogonal approaches, clear identification of specific sheddases","pmids":["19574220"],"is_preprint":false},{"year":2011,"finding":"Neutrophil elastase (NE) cleaves murine BP180 within the extracellular immunodominant domain at amino acid positions 506 and 561, generating peptide p561 which is chemotactic for neutrophils in vitro and in vivo; NE also directly cleaves native human BP180 trimer; NE injection in mouse skin recruits neutrophils, blocked by alpha-1 proteinase inhibitor.","method":"In vitro proteolysis with recombinant NE, mass spectrometry identification of cleavage sites, neutrophil chemotaxis assays, in vivo mouse skin injection, NE inhibitor experiment","journal":"Matrix Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro proteolysis with site identification plus in vivo validation, multiple orthogonal methods","pmids":["21979170"],"is_preprint":false},{"year":2000,"finding":"Anti-BP180 autoantibodies trigger a signal transduction event in keratinocytes that leads to production and secretion of IL-6 and IL-8 (but not IL-1alpha, IL-1beta, TNF-alpha, IL-10, or MCP-1); this effect is BP180-dependent, as it requires reactivity to the NC16A domain and does not occur in BP180-deficient keratinocytes from a GABEB patient.","method":"Treatment of cultured human keratinocytes with BP IgG, cytokine ELISA, mRNA analysis, antibody depletion experiments, BP180-deficient keratinocytes as negative control","journal":"The Journal of Investigative Dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — isogenic control (BP180-deficient cells), antibody depletion, protein and mRNA level measurement, multiple cytokines tested, single lab","pmids":["11069622"],"is_preprint":false},{"year":2008,"finding":"Human anti-BP180NC16A autoantibodies induce BP-like subepidermal blistering in humanized mice (NC16A+/+); F(ab')2 fragments that cannot activate complement are not pathogenic; complement depletion, mast cell activation blockade, or neutrophil depletion prevent blister formation, establishing that the humoral anti-BP180 response depends on complement, mast cells, and neutrophils.","method":"Humanized knock-in mouse model (murine NC14A replaced with human NC16A), passive transfer of IgG and F(ab')2, complement depletion, mast cell inhibition, neutrophil depletion","journal":"Journal of Autoimmunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic humanized mouse model, multiple targeted depletions, replicated pathogenic mechanism","pmids":["18922680"],"is_preprint":false},{"year":2010,"finding":"COL17A1 (collagen XVII) functions as a cell-matrix adhesion molecule by binding to laminin 332; COL17-expressing SK-MEL1 and K562 cells preferentially adhere to laminin 332 substrate with >7-fold greater adhesive force than COL17-negative cells; adhesion is abolished by siRNA knockdown of COL17 or blocking antibodies to COL17 or laminin 332.","method":"Ectopic expression of COL17 in adherence-incompetent cell lines, quantitative cell adhesion assay, siRNA knockdown, antibody blocking","journal":"Matrix Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function expression, siRNA knockdown, and antibody blocking in multiple cell lines; single lab","pmids":["21034821"],"is_preprint":false},{"year":1998,"finding":"BP180 is required for correct BP230 localization into hemidesmosome-like structures; reexpression of BP180 in BP180-deficient GABEB keratinocytes causes BP230 to redistribute from diffuse cytoplasmic distribution to HD-like structures; a 36-amino-acid N-terminal cytoplasmic deletion of BP180 abolishes this effect; BP180 deletion mutant lacking the collagenous extracellular domain still promotes BP230 relocalization.","method":"Immortalized GABEB keratinocytes, transfection of wild-type and deletion mutant BP180, immunofluorescence","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic rescue experiment with deletion mutagenesis in disease-relevant cells, single lab","pmids":["9521865"],"is_preprint":false},{"year":2016,"finding":"DNA damage response in hair follicle stem cells (HFSCs) causes proteolysis of COL17A1, triggering HFSC aging characterized by loss of stemness and epidermal commitment; HFSCs are cyclically eliminated through terminal epidermal differentiation causing hair follicle miniaturization; Col17a1 deficiency recapitulates aging and forced maintenance of COL17A1 prevents it.","method":"In vivo fate analysis, Col17a1 knockout mice, COL17A1 forced expression, DNA damage response analysis, immunofluorescence, lineage tracing","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function, gain-of-function, in vivo fate tracing, multiple experimental approaches, validated in both mice and humans","pmids":["26912707"],"is_preprint":false},{"year":2013,"finding":"BP-IgG induces internalization of BP180 via a macropinocytic pathway in epithelial cells; BP-IgG treatment decreases adhesive strength of cells to substrate, and a macropinocytosis inhibitor rescues BP-IgG-induced reduction in adhesive strength; BP180-GFP co-internalizes with early endosomal antigen-1 after antibody clustering.","method":"GFP-tagged BP180 live imaging, endocytosis inhibitors, fluid-uptake assay, adhesion assay in 804G cells and human keratinocytes","journal":"The American Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple endocytosis inhibitors, fluid-uptake assay, functional adhesion readout, single lab","pmids":["23337823"],"is_preprint":false},{"year":2018,"finding":"BP180 dysfunction (ΔNC16A mice lacking functional BP180) causes spontaneous skin inflammatory disease with severe itch, defective skin barrier, infiltrating immune cells, elevated serum IgE, and increased TSLP expression; itch is independent of adaptive immunity and histamine but dependent on TSLP produced by keratinocytes; COL17A1 thus regulates skin inflammation via TSLP independently of adaptive immunity.","method":"BP180-dysfunctional (ΔNC16A) knock-in mouse model, adaptive immunity-deficient cross, histamine pathway analysis, TSLP measurement, keratinocyte TSLP expression","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with mechanistic dissection (adaptive immunity, histamine, TSLP pathway), multiple orthogonal experiments","pmids":["29866844"],"is_preprint":false},{"year":2021,"finding":"EGFR activation drives keratinocyte stem cell motility by inhibiting COL17A1 proteolysis through secretion of TIMP1; COL17A1 directly regulates keratinocyte stem cell motility and collective cell migration by coordinating actin and keratin filament networks; age-associated decline of EGFR signaling reduces COL17A1 levels and impairs skin regeneration.","method":"Live-imaging, receptor tyrosine kinase array, EGFR activation/inhibition culture experiments, TIMP1 measurement, CRISPR COL17A1 knockout, computer simulation, actin/keratin cytoskeletal analysis","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including live imaging, genetic knockout, pathway inhibition, and cytoskeletal readouts in a single study","pmids":["34550317"],"is_preprint":false},{"year":1999,"finding":"BP180 N-terminal intracellular domain (amino acids 13–25) interacts with p120ctn catenin isoforms 1–3 (but not isoform 4) via a domain encoded by exons 5–6 of p120ctn; confirmed by yeast two-hybrid and in vitro protein-protein interaction assay.","method":"Yeast two-hybrid system, in vitro protein-protein interaction assay","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — two orthogonal methods (yeast two-hybrid + in vitro assay) but single lab, no cell-based functional validation of the interaction","pmids":["10321838"],"is_preprint":false},{"year":2012,"finding":"COL17A1 modulates keratinocyte IL-8 proinflammatory response via NF-kappaB; COL17-deficient EK (from JEB patient or shRNA knockdown) show abnormally high IL-8 after LPS, UV-B, or TNF treatment; restoration of COL17 normalizes LPS-induced IL-8; NF-kappaB inhibition normalizes IL-8 in COL17-negative cells; the effect is not dependent on alpha6beta4 integrin.","method":"JEB patient keratinocytes, shRNA knockdown, COL17 re-expression, NF-kappaB reporter assay, siRNA knockdown of alpha6/beta4 integrin subunits","journal":"Experimental Dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (patient cells + shRNA), gain-of-function (re-expression), NF-kappaB reporter, integrin dependency tested; single lab","pmids":["22775995"],"is_preprint":false},{"year":2017,"finding":"COL17A1 is a novel transcriptional target of p53; p53-binding sequences were identified in the COL17A1 intron by reporter assay and ChIP; COL17A1 expression increases in a p53-dependent manner; overexpression of COL17A1 in MDA-MB-231 cells reduces migration and invasion in vitro.","method":"ChIP assay, reporter assay, cDNA microarray, ectopic COL17A1 overexpression, migration/invasion assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay for transcriptional regulation, functional migration/invasion assay; single lab","pmids":["28915553"],"is_preprint":false},{"year":2021,"finding":"COL17A1 and CD44 co-accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells; COL17A1 and CD44 suppress mitochondrial membrane potential and ROS production, promoting resistance to ferroptosis upon cell extrusion and thereby supporting multilayered transformed epithelial structures; COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I via succinate; CD44 regulates membrane accumulation of COL17A1.","method":"Plasma membrane protein screening, CRISPR-knockout, metabolome analysis, ROS measurement, cell extrusion assay, ferroptosis assay","journal":"Current Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with metabolomics and functional ferroptosis/ROS assays, multiple orthogonal methods, single lab","pmids":["34087104"],"is_preprint":false},{"year":1992,"finding":"TGF-beta1 and TGF-beta2 (10 ng/ml) up-regulate BPAG2/COL17A1 mRNA levels (up to 4.6-fold) in normal keratinocytes, with greater effect in low-calcium conditions; transformed cell lines show extremely low baseline BPAG2 expression.","method":"Northern hybridization, in situ hybridization, TGF-beta treatment of normal and transformed keratinocytes","journal":"The Journal of Investigative Dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single mRNA-level measurement method (Northern blot), no mechanistic follow-up of the TGF-beta pathway, single lab","pmids":["1401998"],"is_preprint":false}],"current_model":"COL17A1/BP180 is a type II transmembrane hemidesmosomal collagen that forms an elongated homotrimeric structure with an intracellular N-terminus, a transmembrane domain, and a long extracellular C-terminal collagenous domain projecting through the lamina lucida to the lamina densa where it loops back; it assembles the hemidesmosome by binding alpha6beta4 integrin (via NC16A ectodomain and cytoplasmic domain), BP230 and plectin (via its cytoplasmic domain), and laminin-332 (via the ectodomain), and is constitutively shed from the cell surface by ADAM9 and ADAM10 (and further cleaved by neutrophil elastase during inflammation); anti-BP180 IgG induces IL-6/IL-8 secretion from keratinocytes, triggers macropinocytic BP180 internalization, and drives subepidermal blistering via complement, mast cells, and neutrophils; DNA-damage-induced COL17A1 proteolysis in hair follicle stem cells drives their epidermal commitment and hair follicle aging, while EGFR-TIMP1 signaling stabilizes COL17A1 to promote keratinocyte stem cell motility and skin regeneration; COL17A1 also regulates keratinocyte NF-kappaB-dependent IL-8 responses and is a p53 transcriptional target that inhibits breast cancer cell migration."},"narrative":{"mechanistic_narrative":"COL17A1 (BP180/BPAG2) is a type II transmembrane collagen that nucleates the keratinocyte hemidesmosome, anchoring basal epithelial cells to the underlying basement membrane [PMID:1324962, PMID:8228259]. It is synthesized with an intracellular N-terminus, a single transmembrane signal-anchor, and a long C-terminal ectodomain composed of multiple collagen triple-helical domains separated by non-collagenous linkers [PMID:1846881, PMID:1324962]; the secreted ectodomain assembles as a stable, highly extended homotrimer [PMID:9220968] that projects through the lamina lucida and loops back into the lamina densa, where its C-terminus lies closer to the membrane than its mid-ectodomain [PMID:9182819, PMID:9242508, PMID:11069628]. The molecule bridges the cell and the matrix on both faces: its cytoplasmic domain binds beta4 and alpha6 integrin, BP230, and plectin to recruit the protein into and stabilize the hemidesmosome [PMID:7790367, PMID:9500991, PMID:10637308, PMID:12482924], while its NC16A ectodomain engages alpha6 integrin and its distal ectodomain binds laminin-332 to mediate cell-matrix adhesion [PMID:9856810, PMID:21034821]. The ectodomain is constitutively shed at the cell surface as a 120-kDa fragment by ADAM9 and ADAM10, a cleavage that depends on the conformational integrity of the NC16A linker, and is further proteolyzed by neutrophil elastase during inflammation, generating neutrophil-chemotactic peptides [PMID:9545306, PMID:15047704, PMID:19574220, PMID:21979170]. Beyond adhesion, COL17A1 levels gate stem cell behavior and tissue homeostasis: DNA-damage-induced proteolysis of COL17A1 drives hair follicle stem cell differentiation and aging, while EGFR-TIMP1 signaling stabilizes COL17A1 to coordinate actin and keratin networks and sustain keratinocyte stem cell motility and skin regeneration [PMID:26912707, PMID:34550317]. COL17A1 also restrains keratinocyte inflammatory output, suppressing NF-kappaB-dependent IL-8 responses and limiting TSLP-driven skin inflammation independently of integrin or adaptive immunity [PMID:29866844, PMID:22775995], and acts as a p53 transcriptional target that inhibits breast cancer cell migration [PMID:28915553]. Autoantibodies against the NC16A domain define its role in bullous pemphigoid, triggering IL-6/IL-8 secretion and macropinocytic internalization of BP180 and driving complement-, mast cell-, and neutrophil-dependent subepidermal blistering [PMID:11069622, PMID:18922680, PMID:23337823].","teleology":[{"year":1992,"claim":"Established the fundamental architecture of COL17A1 as a transmembrane collagen, defining how a structural matrix protein can be membrane-anchored.","evidence":"cDNA cloning and primary structural analysis predicting a type II transmembrane topology with a collagenous ectodomain","pmids":["1324962","1846881"],"confidence":"High","gaps":["Topology predicted from sequence required ultrastructural confirmation","Trimeric assembly state not yet established"]},{"year":1997,"claim":"Resolved the orientation and conformation of the protein, showing the ectodomain is an extended homotrimer projecting through the lamina lucida into the lamina densa.","evidence":"Biophysical analysis of a secreted recombinant ectodomain plus immunoelectron microscopy with domain-specific antibodies in tissue","pmids":["8228259","9220968","9182819","9242508"],"confidence":"High","gaps":["Whether the ectodomain folds back into a loop in vivo not yet directly shown","Trimerization signals within the molecule not mapped"]},{"year":2000,"claim":"Mapped the intracellular interaction network that recruits COL17A1 into the hemidesmosome, identifying integrins, BP230, plectin, and p120ctn as cytoplasmic partners.","evidence":"Yeast two-hybrid, deletion mutagenesis, co-immunoprecipitation, and dominant-negative cell transfection assays across multiple cell lines","pmids":["7790367","9087447","9500991","10637308","10321838","9521865"],"confidence":"Medium","gaps":["Most interactions mapped by yeast two-hybrid without structural validation","p120ctn interaction lacks cell-based functional readout","Stoichiometry of the assembled complex unresolved"]},{"year":2000,"claim":"Demonstrated COL17A1 acts as a bona fide cell-matrix adhesion molecule on its extracellular face, binding alpha6 integrin via NC16A and laminin-332 via its distal ectodomain.","evidence":"Peptide inhibition and recombinant interaction assays plus gain-of-function adhesion assays with siRNA and antibody blocking","pmids":["9856810","21034821"],"confidence":"High","gaps":["Precise laminin-332 binding site on COL17A1 not mapped","Relative contribution of NC16A-integrin versus ectodomain-laminin adhesion in vivo unclear"]},{"year":2009,"claim":"Identified the proteases and structural requirements for constitutive ectodomain shedding, linking NC16A conformation to sheddase recognition.","evidence":"Deletion mutagenesis and shedding assays plus Adam9/Adam10 knockout keratinocytes with selective inhibitors and H2O2 stimulation","pmids":["9545306","15047704","19574220"],"confidence":"High","gaps":["Physiological cues controlling shedding rate beyond oxidative stress not fully defined","Functional consequences of the released 120-kDa fragment not established"]},{"year":2011,"claim":"Established neutrophil elastase as a distinct inflammatory protease that cleaves COL17A1 to generate chemotactic peptides, connecting proteolysis to immune amplification.","evidence":"In vitro proteolysis with cleavage-site mapping by mass spectrometry, chemotaxis assays, and in vivo mouse skin injection with inhibitor","pmids":["11710917","21979170"],"confidence":"High","gaps":["In vivo abundance of chemotactic p561 peptide in human disease not quantified","Crosstalk between constitutive ADAM shedding and inflammatory elastase cleavage unresolved"]},{"year":2013,"claim":"Defined COL17A1 as the autoantigen driving bullous pemphigoid, showing anti-NC16A antibodies are both signaling triggers and effectors of blistering.","evidence":"Keratinocyte cytokine assays, humanized knock-in mouse passive transfer with complement/mast cell/neutrophil depletion, and live imaging of antibody-induced internalization","pmids":["11069622","18922680","23337823"],"confidence":"High","gaps":["Receptor/signaling pathway coupling antibody binding to IL-6/IL-8 secretion not identified","Link between macropinocytic internalization and complement-dependent blistering not integrated"]},{"year":2018,"claim":"Revealed cell-autonomous regulatory roles for COL17A1 in restraining keratinocyte inflammation independently of its structural adhesion function.","evidence":"JEB patient cells and shRNA knockdown with NF-kappaB reporter and integrin-dependency tests; DeltaNC16A mouse model dissecting TSLP, histamine, and adaptive immunity","pmids":["22775995","29866844"],"confidence":"Medium","gaps":["Molecular mechanism by which COL17A1 suppresses NF-kappaB unknown","How a transmembrane collagen signals to control TSLP not defined"]},{"year":2021,"claim":"Connected COL17A1 stability and proteolysis to stem cell fate and tissue regeneration, positioning it as a homeostatic rheostat in epidermal and hair follicle stem cells.","evidence":"Col17a1 knockout/forced-expression mice with lineage tracing and DNA-damage analysis; live imaging, CRISPR knockout, and EGFR-TIMP1 pathway dissection with cytoskeletal readouts","pmids":["26912707","34550317"],"confidence":"High","gaps":["Protease responsible for DNA-damage-induced COL17A1 cleavage in HFSCs not identified","Mechanism linking COL17A1 to coordinated actin/keratin dynamics unresolved"]},{"year":2021,"claim":"Extended COL17A1 function to cancer, implicating it in p53-dependent migration suppression and in metabolic resistance to ferroptosis in transformed epithelia.","evidence":"ChIP and reporter assays with migration/invasion readouts; plasma membrane screening, CRISPR knockout, and metabolome/ROS/ferroptosis assays with CD44","pmids":["28915553","34087104"],"confidence":"Medium","gaps":["How a hemidesmosomal collagen influences mitochondrial metabolism mechanistically unclear","Whether the p53-COL17A1 axis and CD44-COL17A1 axis are connected unknown"]},{"year":null,"claim":"The signaling mechanism by which COL17A1 transduces extracellular cues into intracellular outcomes (NF-kappaB suppression, TSLP control, stem cell fate, mitochondrial metabolism) remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No receptor or adaptor coupling COL17A1 status to intracellular signaling identified","Protease specificity governing context-dependent COL17A1 cleavage outcomes not resolved","Structural basis of the trimeric ectodomain loop and its partner-binding surfaces unsolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[5,20]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[18,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,10]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[11,12,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,6,8]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[11,12,20]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,5,8,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,19,24,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[22,25]}],"complexes":["hemidesmosome"],"partners":["ITGA6","ITGB4","DST","PLEC","LAMA3","CTNND1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UMD9","full_name":"Collagen alpha-1(XVII) chain","aliases":["180 kDa bullous pemphigoid antigen 2","Bullous pemphigoid antigen 2"],"length_aa":1497,"mass_kda":150.4,"function":"May play a role in the integrity of hemidesmosome and the attachment of basal keratinocytes to the underlying basement membrane The 120 kDa linear IgA disease antigen is an anchoring filament component involved in dermal-epidermal cohesion. 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IL-8.","date":"2012","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/22775995","citation_count":27,"is_preprint":false},{"pmid":"34830116","id":"PMC_34830116","title":"BP180/Collagen XVII: A Molecular View.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34830116","citation_count":26,"is_preprint":false},{"pmid":"8432531","id":"PMC_8432531","title":"Chromosomal localization of mouse bullous pemphigoid antigens. 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of recombinant fusion protein\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay confirming collagenous domain identity, single lab, single study\",\n      \"pmids\": [\"1846881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"BP180/COL17A1 is a type II transmembrane protein with an intracellular N-terminus and a long C-terminal extracellular collagenous domain consisting of 15 collagen domains separated by non-collagenous sequences; a transmembrane domain located 76 amino acids upstream of the collagenous region acts as a signal-anchor directing the C-terminal collagenous segment to the cell exterior.\",\n      \"method\": \"cDNA cloning and primary structural analysis, open reading frame prediction\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — complete structural prediction confirmed by multiple subsequent experimental studies and disease mutations; independently replicated\",\n      \"pmids\": [\"1324962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"BP180/BPAG2 autoantibody-reactive region (NC16A, non-collagenous domain) is localized extracellularly to the epidermal basal lamina immediately adjacent to the hemidesmosome, confirming type II transmembrane orientation with the C-terminal collagenous domain projecting into the basal lamina.\",\n      \"method\": \"Bacterial fusion protein expression, immunoblotting, immunoadsorption, immunofluorescence with affinity-purified antiserum\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunoadsorption and localization with affinity-purified antibody, replicated across multiple disease sera and subsequent studies\",\n      \"pmids\": [\"8228259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The BP180 ectodomain exists as an elongated, flexible homotrimeric structure; a recombinant secreted form (sec180e) assembles as a stable homotrimer prior to secretion, with a Stokes radius of 13.6 nm, sedimentation coefficient of 6.5 S, and frictional ratio of 3.01, indicating highly extended conformation; native BP180 from human epidermis also exists in a heat-labile, SDS-stable high-molecular-mass complex.\",\n      \"method\": \"Gel filtration, sedimentation analysis, pulse-chase, chemical cross-linking, COS-1 cell expression\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biophysical methods (gel filtration, sedimentation, cross-linking) in a single rigorous study confirming homotrimeric assembly\",\n      \"pmids\": [\"9220968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"BP180/COL17A1 cytoplasmic domain interacts with the alpha6 integrin subunit; a deletion mutant lacking the extracellular collagenous domains (D1) co-precipitates with alpha6 integrin in HT1080 transfectants, and a 36-amino-acid N-terminal cytoplasmic deletion (D1-36N) disrupts polarization, while deletion of the 27-aa non-collagenous extracellular juxtamembrane domain (D1-27C) prevents co-distribution with hemidesmosomal components.\",\n      \"method\": \"Transfection of deletion mutants into 804G, FG, and HT1080 cells; co-immunoprecipitation; immunofluorescence localization\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation and systematic deletion mutagenesis in multiple cell lines, single lab\",\n      \"pmids\": [\"7790367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BP180 interacts with alpha6 integrin via the non-collagenous NC16A extracellular domain (residues 506-519); this interaction is necessary for hemidesmosome assembly, as a 14-mer peptide spanning this region inhibits the BP180/alpha6 interaction in yeast two-hybrid and recombinant assays and blocks hemidesmosome assembly in 804G cells.\",\n      \"method\": \"Yeast two-hybrid, recombinant protein interaction assay, peptide inhibition, cell culture hemidesmosome assembly assay\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted interaction with mutagenesis-equivalent peptide inhibition plus cell-based functional assay, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"9856810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The intracellular domain of BP180 (amino acids 13–89, including a predicted N-terminal beta-sheet) directly interacts with the beta4 integrin subunit intracellular domain (requiring the connecting segment, second pair of FNIII repeats, and tail region of beta4) as established by yeast two-hybrid analysis.\",\n      \"method\": \"Yeast two-hybrid system with serial deletion constructs\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP equivalent (yeast two-hybrid), single lab, single method\",\n      \"pmids\": [\"9500991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"BP180 cytoplasmic domain contains sufficient information for recruitment into hemidesmosomes; a 265-amino-acid segment spanning the central and N-terminal portions of the cytoplasmic domain mediates hemidesmosomal localization; co-localization with alpha6beta4 requires sequences within the cytoplasmic tail of beta4 (specifically the C-terminal half and the tyrosine activation motif).\",\n      \"method\": \"Transfection of wild-type and deletion mutant cDNA constructs into 804G and COS-7 cells; immunofluorescence localization\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic deletion mutagenesis with cell localization readout, multiple constructs, single lab\",\n      \"pmids\": [\"9087447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The N-terminal domain of BP180 directly binds the N-terminal domain of BP230; expression of the BP230 N-terminus in 804G cells disrupts BP180 distribution at hemidesmosome sites, competing with endogenous BP230 for BP180 binding, thereby demonstrating that this interaction is required for BP180 incorporation into the hemidesmosome.\",\n      \"method\": \"Yeast two-hybrid, recombinant protein binding, cell transfection with dominant-negative fragment\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus recombinant protein interaction plus dominant-negative cell transfection, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"10637308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BP180 binds both BP230 and plectin via the Y subdomain of their N-terminal plakin domains interacting with residues 145–230 of the BP180 cytoplasmic domain; different but overlapping sequences on BP180 mediate binding to beta4 integrin (which associates via its third FNIII repeat); BP230 localization into hemidesmosome-like structures depends on its Z-Y subdomains and requires available BP180.\",\n      \"method\": \"Yeast two-hybrid, cell transfection assays, domain mapping\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain mapping by yeast two-hybrid and cell-transfection, single lab, multiple interaction partners mapped\",\n      \"pmids\": [\"12482924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BP180 is constitutively cleaved on the cell surface to release a 120-kDa collagenous extracellular fragment (LAD-1); the cleavage product lacks the globular head present in intact BP180 and is detectable in culture medium and in vivo in bovine skin basement membrane; it is recognized by a monoclonal antibody (1337) that binds an epitope exposed only upon cleavage.\",\n      \"method\": \"Immunofluorescence microscopy, immunoprecipitation, rotary shadow electron microscopy, immunoblotting\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical purification, electron microscopy, and cell-based secretion assay demonstrating constitutive ectodomain cleavage in vitro and in vivo\",\n      \"pmids\": [\"9545306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The BP180 extracellular domain projects through the lamina lucida to the lamina densa; immuno-electron microscopy with antibodies to the NC16A (membrane-proximal) domain localizes to the upper lamina lucida, whereas antibodies to the C-terminal region localize to the lower lamina lucida/lamina densa interface, co-localizing with anchoring filaments and laminin-5.\",\n      \"method\": \"Immunoelectron microscopy, immunogold localization, immunoadsorption\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct ultrastructural localization of distinct BP180 domains using multiple antibodies, replicated across multiple patient sera and rabbit antisera\",\n      \"pmids\": [\"9182819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The C-terminus (distal ectodomain) of BPAG2/COL17A1 localizes within the lamina densa, 41 nm beneath the plasma membrane of basal keratinocytes, and the extracellular domain runs along anchoring filaments; this was established using anti-BV4 IgG raised against a baculovirus-expressed C-terminal recombinant of BPAG2.\",\n      \"method\": \"Baculovirus expression, affinity purification, immunogold electron microscopy (pre- and post-embedding)\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct immunogold EM with pre- and post-embedding methods quantifying position of C-terminus in tissue\",\n      \"pmids\": [\"9242508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In vivo, the extracellular domain of BPAG2 has at least one loop structure in the lamina densa; immunogold EM with antibodies to intracellular head (20 nm from membrane), mid-extracellular portion (~amino acids 1000–1320, 65 nm from membrane), and C-terminal end (~amino acids 1320–1500, 39 nm from membrane) demonstrates that the C-terminal end is closer to the plasma membrane than the mid-extracellular region, implying a loop.\",\n      \"method\": \"Low temperature post-embedding immunoelectron microscopy with three domain-specific monoclonal antibodies\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous immunogold EM method but single lab, single study\",\n      \"pmids\": [\"11069628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Neutrophil elastase (NE) directly cleaves the extracellular collagenous domain of BP180 in human bullous pemphigoid lesions and blister fluid; NE but not proMMP-9 (which remains inactive in blister fluid, where TIMP-1 levels are high) is responsible for direct BP180 proteolysis during blister formation.\",\n      \"method\": \"In vitro proteolysis of recombinant BP180 with recombinant MMP-9, NE, and blister fluid; inhibition with chloromethylketone (elastase inhibitor) or batimastat (MMP inhibitor); lesional skin and blister fluid analysis\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro proteolysis with specific inhibitors, biological fluids, multiple patient samples\",\n      \"pmids\": [\"11710917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Shedding of collagen XVII/BP180 ectodomain requires the conformational integrity of the NC16A linker domain; the stretch of amino acids 528–547 within NC16A is critical for sheddase recognition and cleavage; furin does not directly cleave collagen XVII but activates ADAMs; large NC16A deletions preventing shedding also result in lower triple-helix thermal stability.\",\n      \"method\": \"Deletion mutagenesis of NC16A domain, expression in COS-7 cells, shedding assay, secondary structure prediction, triple-helix folding thermal stability assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic deletion mutagenesis with shedding assay and structural analysis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"15047704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM10 and ADAM9 are the major sheddases for collagen XVII/BP180 in primary keratinocytes; constitutive shedding is strongly reduced in Adam10−/− cells and is sensitive to the ADAM10-selective inhibitor GI254023X; Adam9−/− keratinocytes show 55% reduction in constitutive shedding; H2O2 enhances ADAM9 expression and stimulates collagen XVII shedding, an effect absent in Adam9−/− mice; ADAM17 only indirectly affects collagen XVII shedding (phorbol ester stimulation does not increase shedding).\",\n      \"method\": \"Adam10−/− and Adam9−/− knockout keratinocytes, selective ADAM inhibitor GI254023X, H2O2 stimulation, in vivo mouse skin experiments\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with selective inhibitor and in vivo experiments, multiple orthogonal approaches, clear identification of specific sheddases\",\n      \"pmids\": [\"19574220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Neutrophil elastase (NE) cleaves murine BP180 within the extracellular immunodominant domain at amino acid positions 506 and 561, generating peptide p561 which is chemotactic for neutrophils in vitro and in vivo; NE also directly cleaves native human BP180 trimer; NE injection in mouse skin recruits neutrophils, blocked by alpha-1 proteinase inhibitor.\",\n      \"method\": \"In vitro proteolysis with recombinant NE, mass spectrometry identification of cleavage sites, neutrophil chemotaxis assays, in vivo mouse skin injection, NE inhibitor experiment\",\n      \"journal\": \"Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro proteolysis with site identification plus in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"21979170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Anti-BP180 autoantibodies trigger a signal transduction event in keratinocytes that leads to production and secretion of IL-6 and IL-8 (but not IL-1alpha, IL-1beta, TNF-alpha, IL-10, or MCP-1); this effect is BP180-dependent, as it requires reactivity to the NC16A domain and does not occur in BP180-deficient keratinocytes from a GABEB patient.\",\n      \"method\": \"Treatment of cultured human keratinocytes with BP IgG, cytokine ELISA, mRNA analysis, antibody depletion experiments, BP180-deficient keratinocytes as negative control\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic control (BP180-deficient cells), antibody depletion, protein and mRNA level measurement, multiple cytokines tested, single lab\",\n      \"pmids\": [\"11069622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human anti-BP180NC16A autoantibodies induce BP-like subepidermal blistering in humanized mice (NC16A+/+); F(ab')2 fragments that cannot activate complement are not pathogenic; complement depletion, mast cell activation blockade, or neutrophil depletion prevent blister formation, establishing that the humoral anti-BP180 response depends on complement, mast cells, and neutrophils.\",\n      \"method\": \"Humanized knock-in mouse model (murine NC14A replaced with human NC16A), passive transfer of IgG and F(ab')2, complement depletion, mast cell inhibition, neutrophil depletion\",\n      \"journal\": \"Journal of Autoimmunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic humanized mouse model, multiple targeted depletions, replicated pathogenic mechanism\",\n      \"pmids\": [\"18922680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"COL17A1 (collagen XVII) functions as a cell-matrix adhesion molecule by binding to laminin 332; COL17-expressing SK-MEL1 and K562 cells preferentially adhere to laminin 332 substrate with >7-fold greater adhesive force than COL17-negative cells; adhesion is abolished by siRNA knockdown of COL17 or blocking antibodies to COL17 or laminin 332.\",\n      \"method\": \"Ectopic expression of COL17 in adherence-incompetent cell lines, quantitative cell adhesion assay, siRNA knockdown, antibody blocking\",\n      \"journal\": \"Matrix Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function expression, siRNA knockdown, and antibody blocking in multiple cell lines; single lab\",\n      \"pmids\": [\"21034821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BP180 is required for correct BP230 localization into hemidesmosome-like structures; reexpression of BP180 in BP180-deficient GABEB keratinocytes causes BP230 to redistribute from diffuse cytoplasmic distribution to HD-like structures; a 36-amino-acid N-terminal cytoplasmic deletion of BP180 abolishes this effect; BP180 deletion mutant lacking the collagenous extracellular domain still promotes BP230 relocalization.\",\n      \"method\": \"Immortalized GABEB keratinocytes, transfection of wild-type and deletion mutant BP180, immunofluorescence\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic rescue experiment with deletion mutagenesis in disease-relevant cells, single lab\",\n      \"pmids\": [\"9521865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DNA damage response in hair follicle stem cells (HFSCs) causes proteolysis of COL17A1, triggering HFSC aging characterized by loss of stemness and epidermal commitment; HFSCs are cyclically eliminated through terminal epidermal differentiation causing hair follicle miniaturization; Col17a1 deficiency recapitulates aging and forced maintenance of COL17A1 prevents it.\",\n      \"method\": \"In vivo fate analysis, Col17a1 knockout mice, COL17A1 forced expression, DNA damage response analysis, immunofluorescence, lineage tracing\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function, gain-of-function, in vivo fate tracing, multiple experimental approaches, validated in both mice and humans\",\n      \"pmids\": [\"26912707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BP-IgG induces internalization of BP180 via a macropinocytic pathway in epithelial cells; BP-IgG treatment decreases adhesive strength of cells to substrate, and a macropinocytosis inhibitor rescues BP-IgG-induced reduction in adhesive strength; BP180-GFP co-internalizes with early endosomal antigen-1 after antibody clustering.\",\n      \"method\": \"GFP-tagged BP180 live imaging, endocytosis inhibitors, fluid-uptake assay, adhesion assay in 804G cells and human keratinocytes\",\n      \"journal\": \"The American Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple endocytosis inhibitors, fluid-uptake assay, functional adhesion readout, single lab\",\n      \"pmids\": [\"23337823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BP180 dysfunction (ΔNC16A mice lacking functional BP180) causes spontaneous skin inflammatory disease with severe itch, defective skin barrier, infiltrating immune cells, elevated serum IgE, and increased TSLP expression; itch is independent of adaptive immunity and histamine but dependent on TSLP produced by keratinocytes; COL17A1 thus regulates skin inflammation via TSLP independently of adaptive immunity.\",\n      \"method\": \"BP180-dysfunctional (ΔNC16A) knock-in mouse model, adaptive immunity-deficient cross, histamine pathway analysis, TSLP measurement, keratinocyte TSLP expression\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with mechanistic dissection (adaptive immunity, histamine, TSLP pathway), multiple orthogonal experiments\",\n      \"pmids\": [\"29866844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGFR activation drives keratinocyte stem cell motility by inhibiting COL17A1 proteolysis through secretion of TIMP1; COL17A1 directly regulates keratinocyte stem cell motility and collective cell migration by coordinating actin and keratin filament networks; age-associated decline of EGFR signaling reduces COL17A1 levels and impairs skin regeneration.\",\n      \"method\": \"Live-imaging, receptor tyrosine kinase array, EGFR activation/inhibition culture experiments, TIMP1 measurement, CRISPR COL17A1 knockout, computer simulation, actin/keratin cytoskeletal analysis\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including live imaging, genetic knockout, pathway inhibition, and cytoskeletal readouts in a single study\",\n      \"pmids\": [\"34550317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BP180 N-terminal intracellular domain (amino acids 13–25) interacts with p120ctn catenin isoforms 1–3 (but not isoform 4) via a domain encoded by exons 5–6 of p120ctn; confirmed by yeast two-hybrid and in vitro protein-protein interaction assay.\",\n      \"method\": \"Yeast two-hybrid system, in vitro protein-protein interaction assay\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — two orthogonal methods (yeast two-hybrid + in vitro assay) but single lab, no cell-based functional validation of the interaction\",\n      \"pmids\": [\"10321838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"COL17A1 modulates keratinocyte IL-8 proinflammatory response via NF-kappaB; COL17-deficient EK (from JEB patient or shRNA knockdown) show abnormally high IL-8 after LPS, UV-B, or TNF treatment; restoration of COL17 normalizes LPS-induced IL-8; NF-kappaB inhibition normalizes IL-8 in COL17-negative cells; the effect is not dependent on alpha6beta4 integrin.\",\n      \"method\": \"JEB patient keratinocytes, shRNA knockdown, COL17 re-expression, NF-kappaB reporter assay, siRNA knockdown of alpha6/beta4 integrin subunits\",\n      \"journal\": \"Experimental Dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (patient cells + shRNA), gain-of-function (re-expression), NF-kappaB reporter, integrin dependency tested; single lab\",\n      \"pmids\": [\"22775995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COL17A1 is a novel transcriptional target of p53; p53-binding sequences were identified in the COL17A1 intron by reporter assay and ChIP; COL17A1 expression increases in a p53-dependent manner; overexpression of COL17A1 in MDA-MB-231 cells reduces migration and invasion in vitro.\",\n      \"method\": \"ChIP assay, reporter assay, cDNA microarray, ectopic COL17A1 overexpression, migration/invasion assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay for transcriptional regulation, functional migration/invasion assay; single lab\",\n      \"pmids\": [\"28915553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COL17A1 and CD44 co-accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells; COL17A1 and CD44 suppress mitochondrial membrane potential and ROS production, promoting resistance to ferroptosis upon cell extrusion and thereby supporting multilayered transformed epithelial structures; COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I via succinate; CD44 regulates membrane accumulation of COL17A1.\",\n      \"method\": \"Plasma membrane protein screening, CRISPR-knockout, metabolome analysis, ROS measurement, cell extrusion assay, ferroptosis assay\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with metabolomics and functional ferroptosis/ROS assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34087104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"TGF-beta1 and TGF-beta2 (10 ng/ml) up-regulate BPAG2/COL17A1 mRNA levels (up to 4.6-fold) in normal keratinocytes, with greater effect in low-calcium conditions; transformed cell lines show extremely low baseline BPAG2 expression.\",\n      \"method\": \"Northern hybridization, in situ hybridization, TGF-beta treatment of normal and transformed keratinocytes\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single mRNA-level measurement method (Northern blot), no mechanistic follow-up of the TGF-beta pathway, single lab\",\n      \"pmids\": [\"1401998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COL17A1/BP180 is a type II transmembrane hemidesmosomal collagen that forms an elongated homotrimeric structure with an intracellular N-terminus, a transmembrane domain, and a long extracellular C-terminal collagenous domain projecting through the lamina lucida to the lamina densa where it loops back; it assembles the hemidesmosome by binding alpha6beta4 integrin (via NC16A ectodomain and cytoplasmic domain), BP230 and plectin (via its cytoplasmic domain), and laminin-332 (via the ectodomain), and is constitutively shed from the cell surface by ADAM9 and ADAM10 (and further cleaved by neutrophil elastase during inflammation); anti-BP180 IgG induces IL-6/IL-8 secretion from keratinocytes, triggers macropinocytic BP180 internalization, and drives subepidermal blistering via complement, mast cells, and neutrophils; DNA-damage-induced COL17A1 proteolysis in hair follicle stem cells drives their epidermal commitment and hair follicle aging, while EGFR-TIMP1 signaling stabilizes COL17A1 to promote keratinocyte stem cell motility and skin regeneration; COL17A1 also regulates keratinocyte NF-kappaB-dependent IL-8 responses and is a p53 transcriptional target that inhibits breast cancer cell migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COL17A1 (BP180/BPAG2) is a type II transmembrane collagen that nucleates the keratinocyte hemidesmosome, anchoring basal epithelial cells to the underlying basement membrane [#1, #2]. It is synthesized with an intracellular N-terminus, a single transmembrane signal-anchor, and a long C-terminal ectodomain composed of multiple collagen triple-helical domains separated by non-collagenous linkers [#0, #1]; the secreted ectodomain assembles as a stable, highly extended homotrimer [#3] that projects through the lamina lucida and loops back into the lamina densa, where its C-terminus lies closer to the membrane than its mid-ectodomain [#11, #12, #13]. The molecule bridges the cell and the matrix on both faces: its cytoplasmic domain binds beta4 and alpha6 integrin, BP230, and plectin to recruit the protein into and stabilize the hemidesmosome [#4, #6, #8, #9], while its NC16A ectodomain engages alpha6 integrin and its distal ectodomain binds laminin-332 to mediate cell-matrix adhesion [#5, #20]. The ectodomain is constitutively shed at the cell surface as a 120-kDa fragment by ADAM9 and ADAM10, a cleavage that depends on the conformational integrity of the NC16A linker, and is further proteolyzed by neutrophil elastase during inflammation, generating neutrophil-chemotactic peptides [#10, #15, #16, #17]. Beyond adhesion, COL17A1 levels gate stem cell behavior and tissue homeostasis: DNA-damage-induced proteolysis of COL17A1 drives hair follicle stem cell differentiation and aging, while EGFR-TIMP1 signaling stabilizes COL17A1 to coordinate actin and keratin networks and sustain keratinocyte stem cell motility and skin regeneration [#22, #25]. COL17A1 also restrains keratinocyte inflammatory output, suppressing NF-kappaB-dependent IL-8 responses and limiting TSLP-driven skin inflammation independently of integrin or adaptive immunity [#24, #27], and acts as a p53 transcriptional target that inhibits breast cancer cell migration [#28]. Autoantibodies against the NC16A domain define its role in bullous pemphigoid, triggering IL-6/IL-8 secretion and macropinocytic internalization of BP180 and driving complement-, mast cell-, and neutrophil-dependent subepidermal blistering [#18, #19, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the fundamental architecture of COL17A1 as a transmembrane collagen, defining how a structural matrix protein can be membrane-anchored.\",\n      \"evidence\": \"cDNA cloning and primary structural analysis predicting a type II transmembrane topology with a collagenous ectodomain\",\n      \"pmids\": [\"1324962\", \"1846881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Topology predicted from sequence required ultrastructural confirmation\", \"Trimeric assembly state not yet established\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved the orientation and conformation of the protein, showing the ectodomain is an extended homotrimer projecting through the lamina lucida into the lamina densa.\",\n      \"evidence\": \"Biophysical analysis of a secreted recombinant ectodomain plus immunoelectron microscopy with domain-specific antibodies in tissue\",\n      \"pmids\": [\"8228259\", \"9220968\", \"9182819\", \"9242508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the ectodomain folds back into a loop in vivo not yet directly shown\", \"Trimerization signals within the molecule not mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapped the intracellular interaction network that recruits COL17A1 into the hemidesmosome, identifying integrins, BP230, plectin, and p120ctn as cytoplasmic partners.\",\n      \"evidence\": \"Yeast two-hybrid, deletion mutagenesis, co-immunoprecipitation, and dominant-negative cell transfection assays across multiple cell lines\",\n      \"pmids\": [\"7790367\", \"9087447\", \"9500991\", \"10637308\", \"10321838\", \"9521865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most interactions mapped by yeast two-hybrid without structural validation\", \"p120ctn interaction lacks cell-based functional readout\", \"Stoichiometry of the assembled complex unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated COL17A1 acts as a bona fide cell-matrix adhesion molecule on its extracellular face, binding alpha6 integrin via NC16A and laminin-332 via its distal ectodomain.\",\n      \"evidence\": \"Peptide inhibition and recombinant interaction assays plus gain-of-function adhesion assays with siRNA and antibody blocking\",\n      \"pmids\": [\"9856810\", \"21034821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise laminin-332 binding site on COL17A1 not mapped\", \"Relative contribution of NC16A-integrin versus ectodomain-laminin adhesion in vivo unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the proteases and structural requirements for constitutive ectodomain shedding, linking NC16A conformation to sheddase recognition.\",\n      \"evidence\": \"Deletion mutagenesis and shedding assays plus Adam9/Adam10 knockout keratinocytes with selective inhibitors and H2O2 stimulation\",\n      \"pmids\": [\"9545306\", \"15047704\", \"19574220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological cues controlling shedding rate beyond oxidative stress not fully defined\", \"Functional consequences of the released 120-kDa fragment not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established neutrophil elastase as a distinct inflammatory protease that cleaves COL17A1 to generate chemotactic peptides, connecting proteolysis to immune amplification.\",\n      \"evidence\": \"In vitro proteolysis with cleavage-site mapping by mass spectrometry, chemotaxis assays, and in vivo mouse skin injection with inhibitor\",\n      \"pmids\": [\"11710917\", \"21979170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo abundance of chemotactic p561 peptide in human disease not quantified\", \"Crosstalk between constitutive ADAM shedding and inflammatory elastase cleavage unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined COL17A1 as the autoantigen driving bullous pemphigoid, showing anti-NC16A antibodies are both signaling triggers and effectors of blistering.\",\n      \"evidence\": \"Keratinocyte cytokine assays, humanized knock-in mouse passive transfer with complement/mast cell/neutrophil depletion, and live imaging of antibody-induced internalization\",\n      \"pmids\": [\"11069622\", \"18922680\", \"23337823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/signaling pathway coupling antibody binding to IL-6/IL-8 secretion not identified\", \"Link between macropinocytic internalization and complement-dependent blistering not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed cell-autonomous regulatory roles for COL17A1 in restraining keratinocyte inflammation independently of its structural adhesion function.\",\n      \"evidence\": \"JEB patient cells and shRNA knockdown with NF-kappaB reporter and integrin-dependency tests; DeltaNC16A mouse model dissecting TSLP, histamine, and adaptive immunity\",\n      \"pmids\": [\"22775995\", \"29866844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which COL17A1 suppresses NF-kappaB unknown\", \"How a transmembrane collagen signals to control TSLP not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected COL17A1 stability and proteolysis to stem cell fate and tissue regeneration, positioning it as a homeostatic rheostat in epidermal and hair follicle stem cells.\",\n      \"evidence\": \"Col17a1 knockout/forced-expression mice with lineage tracing and DNA-damage analysis; live imaging, CRISPR knockout, and EGFR-TIMP1 pathway dissection with cytoskeletal readouts\",\n      \"pmids\": [\"26912707\", \"34550317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for DNA-damage-induced COL17A1 cleavage in HFSCs not identified\", \"Mechanism linking COL17A1 to coordinated actin/keratin dynamics unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended COL17A1 function to cancer, implicating it in p53-dependent migration suppression and in metabolic resistance to ferroptosis in transformed epithelia.\",\n      \"evidence\": \"ChIP and reporter assays with migration/invasion readouts; plasma membrane screening, CRISPR knockout, and metabolome/ROS/ferroptosis assays with CD44\",\n      \"pmids\": [\"28915553\", \"34087104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a hemidesmosomal collagen influences mitochondrial metabolism mechanistically unclear\", \"Whether the p53-COL17A1 axis and CD44-COL17A1 axis are connected unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The signaling mechanism by which COL17A1 transduces extracellular cues into intracellular outcomes (NF-kappaB suppression, TSLP control, stem cell fate, mitochondrial metabolism) remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or adaptor coupling COL17A1 status to intracellular signaling identified\", \"Protease specificity governing context-dependent COL17A1 cleavage outcomes not resolved\", \"Structural basis of the trimeric ectodomain loop and its partner-binding surfaces unsolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [5, 20]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [18, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 10]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [11, 12, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [11, 12, 20]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 5, 8, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 19, 24, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [22, 25]}\n    ],\n    \"complexes\": [\"hemidesmosome\"],\n    \"partners\": [\"ITGA6\", \"ITGB4\", \"DST\", \"PLEC\", \"LAMA3\", \"CTNND1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}