{"gene":"ADAM11","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1993,"finding":"ADAM11 (originally named MDC) was identified as a novel gene at chromosomal locus 17q21.3 encoding a metalloprotease-like, disintegrin-like, cysteine-rich (MDC) protein of 524 amino acids; two primary breast cancers showed somatic rearrangements disrupting its coding region, implicating it as a candidate tumor suppressor gene.","method":"Genomic cloning from cosmid library, Southern blot analysis of somatic rearrangements in primary breast cancer specimens","journal":"Nature Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic evidence of somatic rearrangement in two tumors, single lab","pmids":["8252040"],"is_preprint":false},{"year":1995,"finding":"The ADAM11 (MDC) gene was shown to consist of 28 exons encoding a modular protein with distinct pro-, metalloprotease-like, disintegrin, cysteine-rich (including an EGF-like repeat), transmembrane, and cytoplasmic domains; two alternatively spliced transcripts were identified, encoding proteins of 769 and 524 amino acids respectively.","method":"cDNA cloning, genomic exon-intron mapping, alternative splicing analysis","journal":"Cytogenetics and Cell Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct structural characterization of gene and transcripts, single lab","pmids":["7956356"],"is_preprint":false},{"year":1998,"finding":"ADAM11 (MDC) was found to have a disrupted zinc-binding motif in its metalloprotease-like domain (rendering it catalytically inactive), and its disintegrin-like domain lacks the RGD sequence present in snake venom disintegrins; ADAM11 mRNA is highly expressed in the brain, analogous to the closely related ADAM22 (MDC2) and ADAM23 (MDC3).","method":"cDNA cloning, sequence analysis, Northern blot analysis","journal":"The Biochemical Journal","confidence":"Medium","confidence_rationale":"Tier 2 — sequence analysis with functional domain annotation and Northern blot, single lab","pmids":["9693107"],"is_preprint":false},{"year":1999,"finding":"Mouse orthologs of ADAM11, ADAM22, and ADAM23 were cloned and mapped to chromosomal loci syntenic with their human counterparts; all three murine ADAMs were highly expressed in the mouse brain by Northern blot, consistent with roles as integrin receptors in neural development.","method":"cDNA cloning, interspecies backcross chromosomal mapping, Northern blot analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct cloning and chromosomal mapping with expression analysis, single lab","pmids":["10433968"],"is_preprint":false},{"year":2002,"finding":"ADAM11 mRNA expression in the adult mouse CNS was localized to neurons throughout the forebrain, brainstem, cerebellar cortex, and spinal cord, as well as peripheral ganglia, retinae, and testes; during development, ADAM11 was differentially expressed in developing PNS, CNS, heart, kidney, eyes, and brown fat, suggesting involvement in neuron-neuron or neuron-glial cell interactions.","method":"In situ hybridization, Northern blot analysis on adult and developing mouse tissues","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by in situ hybridization across developmental stages, single lab","pmids":["12088751"],"is_preprint":false},{"year":2006,"finding":"ADAM11-deficient mice generated by gene targeting showed deficits in hidden water maze learning and rotating rod motor coordination, while visual water maze performance was normal, indicating that ADAM11 plays a signaling or structural role as a cell adhesion molecule at synapses and participates in synaptic regulation underlying spatial learning and motor coordination.","method":"Gene targeting/knockout mouse generation, Morris water maze (visual and hidden tasks), rotating rod behavioral testing, histological analysis","journal":"BMC Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific behavioral phenotypes and normal histology; replicated across multiple behavioral paradigms","pmids":["16504143"],"is_preprint":false},{"year":2006,"finding":"ADAM11-deficient mice showed reduced responses in the formalin paw test and acetic acid writhing test (models of inflammatory and visceral pain) but normal responses in the von Frey and hot plate tests, indicating ADAM11 plays a role in pain transmission and inflammatory nociception.","method":"ADAM11 knockout mice, von Frey test, hot plate test, formalin paw test, acetic acid writhing test","journal":"Brain Research","confidence":"Medium","confidence_rationale":"Tier 2 — KO with specific phenotypic readouts across multiple pain models, single lab","pmids":["16729981"],"is_preprint":false},{"year":2008,"finding":"LGI1 and LGI4 were identified as binding partners of ADAM11 (as well as ADAM22 and ADAM23); binding was demonstrated by immunoprecipitation from mouse brain lysates, mass spectrometric identification, and a quantitative cell-ELISA system, indicating that the LGI-ADAM system involves multiple ADAM receptors and is regulated by cell-type-specific expression.","method":"Immunoprecipitation from mouse brain, mass spectrometric analysis, quantitative cell-ELISA binding assay","journal":"International Journal of Biological Sciences","confidence":"High","confidence_rationale":"Tier 2 — reciprocal IP from native tissue plus orthogonal quantitative binding assay, moderate evidence","pmids":["18974846"],"is_preprint":false},{"year":2015,"finding":"ADAM11 was identified as the first Kv1-interacting protein essential for localizing Kv1.1 and Kv1.2 subunit complexes to the cerebellar basket cell pinceau terminal; in Adam11 mutant mice, Kv1 channels were absent from the distal pinceau terminal while perisomatic GABAergic synaptic release was unaffected, and ultrarapid ephaptic inhibitory synchronization of Purkinje cell firing was abolished, demonstrating that ADAM11-anchored presynaptic Kv1 channels mediate ephaptic (electrical) rather than chemical neurotransmission at this synapse.","method":"Adam11 mutant mice, immunofluorescence and immunoelectron microscopy for Kv1.1/Kv1.2 localization, electrophysiological recording of spontaneous IPSCs, field potential recording of ephaptic inhibitory responses, ultrastructural analysis","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — KO with direct localization of specific channel complexes, electrophysiological functional readouts distinguishing chemical vs. ephaptic transmission, multiple orthogonal methods","pmids":["26269648"],"is_preprint":false}],"current_model":"ADAM11 is a catalytically inactive (disrupted zinc-binding motif), brain-enriched transmembrane ADAM family protein that functions as a cell adhesion/scaffolding molecule: it serves as a receptor for LGI1 and LGI4 ligands in the nervous system, and is essential for localizing Kv1.1/Kv1.2 potassium channel complexes to the cerebellar basket cell pinceau terminal, where these channels mediate ephaptic (non-synaptic electrical) inhibitory control of Purkinje cell firing; loss of ADAM11 impairs spatial learning, motor coordination, and inflammatory nociception in mice."},"narrative":{"teleology":[{"year":1993,"claim":"Identification of ADAM11 as a novel metalloprotease-disintegrin-cysteine-rich gene at 17q21.3 established it as a candidate of interest, initially through somatic rearrangements in breast tumors.","evidence":"Genomic cloning from a cosmid library with Southern blot detection of rearrangements in primary breast cancers","pmids":["8252040"],"confidence":"Medium","gaps":["Tumor-suppressor role never independently validated","No functional assay performed","Only two tumors showed rearrangement"]},{"year":1998,"claim":"Sequence analysis resolved that ADAM11 is catalytically inactive due to a disrupted zinc-binding motif and lacks the RGD disintegrin sequence, redirecting its functional interpretation from a protease toward an adhesion/scaffolding molecule.","evidence":"cDNA cloning and sequence comparison of metalloprotease and disintegrin domains; Northern blot showing high brain expression","pmids":["9693107"],"confidence":"Medium","gaps":["Binding partners unknown","No functional assay demonstrating adhesion activity","Protein-level expression and localization not determined"]},{"year":2002,"claim":"Detailed expression mapping revealed ADAM11 mRNA in neurons across the CNS, PNS, and select non-neural tissues during development, narrowing its likely function to neuron–neuron or neuron–glia interactions.","evidence":"In situ hybridization and Northern blot across adult and developing mouse tissues","pmids":["12088751"],"confidence":"Medium","gaps":["Protein localization at subcellular level not addressed","No loss-of-function data yet available","Cell-type-specific roles unresolved"]},{"year":2006,"claim":"Generation of ADAM11 knockout mice demonstrated that the protein is required for normal spatial learning, motor coordination, and inflammatory nociception, establishing its in vivo physiological importance without overt structural brain abnormalities.","evidence":"Gene-targeted knockout mice tested with Morris water maze, rotating rod, formalin paw, and acetic acid writhing assays","pmids":["16504143","16729981"],"confidence":"High","gaps":["Molecular mechanism underlying behavioral deficits unknown","Synaptic partners unidentified","Pain-signaling pathway not delineated"]},{"year":2008,"claim":"Identification of LGI1 and LGI4 as ligands for ADAM11 established a receptor–ligand system analogous to LGI–ADAM22 interactions, suggesting cell-type-specific signaling through the LGI–ADAM axis.","evidence":"Immunoprecipitation from mouse brain lysates, mass spectrometry, and quantitative cell-ELISA binding assays","pmids":["18974846"],"confidence":"High","gaps":["Downstream signaling events triggered by LGI binding to ADAM11 not characterized","Structural basis of selectivity among ADAM11/22/23 for LGI ligands unknown","In vivo relevance of LGI4–ADAM11 interaction not tested"]},{"year":2015,"claim":"ADAM11 was shown to be the critical anchor for Kv1.1/Kv1.2 channel complexes at the basket cell pinceau, and its loss abolished ephaptic inhibition of Purkinje cells while leaving chemical GABAergic transmission intact — defining ADAM11's primary electrophysiological function.","evidence":"Adam11 mutant mice analyzed by immunofluorescence, immunoelectron microscopy for Kv1 localization, and electrophysiology distinguishing ephaptic vs. chemical transmission","pmids":["26269648"],"confidence":"High","gaps":["Direct physical interaction between ADAM11 and Kv1 subunits not biochemically demonstrated","Whether ADAM11 anchors Kv1 channels at other brain sites is unknown","Relationship between Kv1 anchoring and the spatial learning/nociception phenotypes is unresolved"]},{"year":null,"claim":"Key open questions include whether ADAM11 directly binds Kv1 channels or requires intermediary scaffolding partners, how LGI ligand binding modulates ADAM11's channel-anchoring function, and whether ADAM11 serves analogous scaffolding roles outside the cerebellum.","evidence":"","pmids":[],"confidence":"Low","gaps":["No biochemical reconstitution of ADAM11–Kv1 complex","Structural basis of ADAM11 function unresolved","Role outside cerebellum and in peripheral nociceptive circuits not mechanistically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,5,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,8]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[7,8]}],"complexes":[],"partners":["LGI1","LGI4","KCNA1","KCNA2"],"other_free_text":[]},"mechanistic_narrative":"ADAM11 is a catalytically inactive, brain-enriched member of the ADAM (a disintegrin and metalloproteinase) family that functions as a transmembrane adhesion and scaffolding molecule in the nervous system. Its metalloprotease-like domain lacks a functional zinc-binding motif, and its disintegrin domain lacks the canonical RGD integrin-binding sequence, consistent with non-proteolytic roles in cell–cell interaction [PMID:9693107]. ADAM11 serves as a receptor for the secreted ligands LGI1 and LGI4 [PMID:18974846] and is essential for anchoring Kv1.1/Kv1.2 potassium channel complexes at the cerebellar basket cell pinceau terminal, where these channels mediate ultrarapid ephaptic (non-synaptic electrical) inhibition of Purkinje cell firing [PMID:26269648]. Loss of ADAM11 in mice impairs spatial learning, motor coordination, and inflammatory nociception [PMID:16504143, PMID:16729981]."},"prefetch_data":{"uniprot":{"accession":"O75078","full_name":"Disintegrin and metalloproteinase domain-containing protein 11","aliases":["Metalloproteinase-like, disintegrin-like, and cysteine-rich protein","MDC"],"length_aa":769,"mass_kda":83.4,"function":"Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein. Required for localization of the potassium channel subunit proteins KCNA1/KV1.1 and KCNA2/KV1.2 at cerebellar cortex basket cell distal terminals, is thereby involved in ephaptic inhibitory synchronization of Purkinje cell firing and response to stress (By similarity). Plays a role in spatial learning and motor coordination (By similarity). Involved in the nociceptive pain response to chemical-derived stimulation (By similarity)","subcellular_location":"Presynaptic cell membrane; Perikaryon; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/O75078/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAM11","classification":"Not Classified","n_dependent_lines":133,"n_total_lines":1208,"dependency_fraction":0.11009933774834436},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADAM11","total_profiled":1310},"omim":[{"mim_id":"155120","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 11; ADAM11","url":"https://www.omim.org/entry/155120"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":91.2}],"url":"https://www.proteinatlas.org/search/ADAM11"},"hgnc":{"alias_symbol":[],"prev_symbol":["MDC"]},"alphafold":{"accession":"O75078","domains":[{"cath_id":"3.40.390.10","chopping":"47-173_240-429","consensus_level":"medium","plddt":86.0701,"start":47,"end":429},{"cath_id":"4.10.70.10","chopping":"464-529","consensus_level":"high","plddt":88.7848,"start":464,"end":529},{"cath_id":"-","chopping":"534-675","consensus_level":"high","plddt":92.7288,"start":534,"end":675},{"cath_id":"2.10.25,2.10.25","chopping":"678-715","consensus_level":"medium","plddt":85.7424,"start":678,"end":715}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75078","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75078-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75078-F1-predicted_aligned_error_v6.png","plddt_mean":79.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAM11","jax_strain_url":"https://www.jax.org/strain/search?query=ADAM11"},"sequence":{"accession":"O75078","fasta_url":"https://rest.uniprot.org/uniprotkb/O75078.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75078/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75078"}},"corpus_meta":[{"pmid":"7750517","id":"PMC_7750517","title":"Monodansylcadaverine 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involves multiple receptors regulated by cell-type-specific expression patterns.\",\n      \"method\": \"Immunoprecipitation from mouse brain followed by mass spectrometric analysis, confirmed by quantitative cell-ELISA binding assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays in cell-ELISA system, single lab\",\n      \"pmids\": [\"18974846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM11-deficient mice show deficits in spatial learning (hidden water maze) and motor coordination (rotating rod), while visual water maze performance is normal; ADAM11 is highly expressed in hippocampus and cerebellum and is proposed to function as a cell adhesion molecule at synapses involved in synaptic regulation underlying these behaviors.\",\n      \"method\": \"Gene targeting to generate ADAM11 knockout mice; behavioral testing (water maze, rotating rod); histological analysis of brain\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular/behavioral phenotype, multiple behavioral paradigms\",\n      \"pmids\": [\"16504143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM11-deficient mice show reduced responses in the formalin paw test and acetic acid writhing test (inflammatory/visceral pain) but normal responses in the von Frey and hot plate tests, indicating ADAM11 plays a role in pain transmission and inflammatory pain regulation.\",\n      \"method\": \"Gene targeting (ADAM11 knockout mice); behavioral pain assays (von Frey, hot plate, formalin paw, acetic acid writhing)\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined pain phenotype, single lab\",\n      \"pmids\": [\"16729981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADAM11 is the first identified Kv1-interacting transmembrane protein essential for localizing Kv1.1 and Kv1.2 potassium channel subunit complexes to the cerebellar basket cell pinceau terminal. Loss of ADAM11 selectively eliminates Kv1 channel clusters at the distal pinceau, abolishing ultrarapid ephaptic inhibitory synchronization of Purkinje cell firing without affecting spontaneous GABAergic release from perisomatic boutons.\",\n      \"method\": \"Adam11 mutant mice; immunofluorescence and electron microscopy of pinceau terminals; electrophysiological recording of Purkinje cell firing; in vivo ephaptic current measurements\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic KO with multiple orthogonal methods (EM, immunofluorescence, electrophysiology), clear mechanistic dissection of ephaptic vs. GABAergic function\",\n      \"pmids\": [\"26269648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ADAM11 mRNA is expressed throughout the CNS (forebrain, brainstem, cerebellar cortex, spinal cord) and peripheral nervous system exclusively in neurons, with differential expression during pre- and perinatal development, suggesting a widespread role in neuron-neuron or neuron-glial interactions.\",\n      \"method\": \"In situ hybridization and Northern blot analysis of adult and developing mouse brain and peripheral tissues\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization by in situ hybridization, developmental staging, single lab\",\n      \"pmids\": [\"12088751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human MDC (ADAM11) gene consists of 28 exons encoding a protein of 769 amino acids (or alternatively 524 aa by alternative splicing), with exon-encoded functional domains including a proprotein domain, metalloprotease-like domain, disintegrin domain, cysteine-rich/EGF-like domain, transmembrane domain, and cytoplasmic domain.\",\n      \"method\": \"cDNA cloning, exon-intron mapping, alternative splicing analysis\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic/cDNA structural characterization, defines domain architecture\",\n      \"pmids\": [\"7956356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse ADAM11 (ortholog of human MDC/ADAM11), along with ADAM22 and ADAM23, is highly expressed in the mouse brain; chromosomal locations of murine ADAM11, ADAM22, and ADAM23 are syntenic with their human orthologs, consistent with conserved neural function.\",\n      \"method\": \"Northern blot analysis; interspecies backcross chromosomal mapping\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — expression and mapping data, single lab\",\n      \"pmids\": [\"10433968\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM11 is a catalytically inactive transmembrane disintegrin that functions in the nervous system as a cell adhesion and scaffolding molecule: it binds LGI1/LGI4 ligands, is essential for clustering Kv1.1/Kv1.2 potassium channels at the cerebellar basket cell pinceau to enable ephaptic inhibition of Purkinje cell firing, and is required in the hippocampus and cerebellum for spatial learning, motor coordination, and inflammatory pain transmission.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers about the canonical protein ADAM11 (also known as MDC, a brain-expressed non-catalytic ADAM family member).\n\n**Classification:**\n\nKEEP papers about canonical ADAM11:\n- [13] PMID:18974846 - LGI1/LGI4 bind ADAM22, ADAM23, ADAM11\n- [28] PMID:10433968 - Cloning/mapping mouse ADAM11, ADAM22, ADAM23\n- [41] PMID:16504143 - ADAM11-deficient mice, spatial learning/motor coordination\n- [48] PMID:26269648 - ADAM11 localizes Kv1 channels at cerebellar basket cell pinceau\n- [53] PMID:12088751 - ADAM11 developmental expression in nervous system\n- [66] PMID:16729981 - Altered nociception in ADAM11-deficient mice\n- [34] PMID:7956356 - Human MDC gene (ADAM11) exon-intron structure\n- [15 from curated] PMID:9693107 - MDC2/MDC3 paper describing MDC/ADAM11 as brain-expressed, disrupted zinc-binding motif\n- [13 from curated] PMID:8252040 - Original MDC (ADAM11) gene discovery\n\nEXCLUDE: All papers about CCL22/MDC chemokine, MDC-L (ADAM28), ADAM-9, ADAM-15, MDC drugs, Musca domestica cecropin, myeloid dendritic cells (mDC), MDC bioinformatics tools, etc.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"ADAM11 (originally named MDC) was identified as a novel gene at chromosomal locus 17q21.3 encoding a metalloprotease-like, disintegrin-like, cysteine-rich (MDC) protein of 524 amino acids; two primary breast cancers showed somatic rearrangements disrupting its coding region, implicating it as a candidate tumor suppressor gene.\",\n      \"method\": \"Genomic cloning from cosmid library, Southern blot analysis of somatic rearrangements in primary breast cancer specimens\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic evidence of somatic rearrangement in two tumors, single lab\",\n      \"pmids\": [\"8252040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The ADAM11 (MDC) gene was shown to consist of 28 exons encoding a modular protein with distinct pro-, metalloprotease-like, disintegrin, cysteine-rich (including an EGF-like repeat), transmembrane, and cytoplasmic domains; two alternatively spliced transcripts were identified, encoding proteins of 769 and 524 amino acids respectively.\",\n      \"method\": \"cDNA cloning, genomic exon-intron mapping, alternative splicing analysis\",\n      \"journal\": \"Cytogenetics and Cell Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct structural characterization of gene and transcripts, single lab\",\n      \"pmids\": [\"7956356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ADAM11 (MDC) was found to have a disrupted zinc-binding motif in its metalloprotease-like domain (rendering it catalytically inactive), and its disintegrin-like domain lacks the RGD sequence present in snake venom disintegrins; ADAM11 mRNA is highly expressed in the brain, analogous to the closely related ADAM22 (MDC2) and ADAM23 (MDC3).\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blot analysis\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — sequence analysis with functional domain annotation and Northern blot, single lab\",\n      \"pmids\": [\"9693107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse orthologs of ADAM11, ADAM22, and ADAM23 were cloned and mapped to chromosomal loci syntenic with their human counterparts; all three murine ADAMs were highly expressed in the mouse brain by Northern blot, consistent with roles as integrin receptors in neural development.\",\n      \"method\": \"cDNA cloning, interspecies backcross chromosomal mapping, Northern blot analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cloning and chromosomal mapping with expression analysis, single lab\",\n      \"pmids\": [\"10433968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ADAM11 mRNA expression in the adult mouse CNS was localized to neurons throughout the forebrain, brainstem, cerebellar cortex, and spinal cord, as well as peripheral ganglia, retinae, and testes; during development, ADAM11 was differentially expressed in developing PNS, CNS, heart, kidney, eyes, and brown fat, suggesting involvement in neuron-neuron or neuron-glial cell interactions.\",\n      \"method\": \"In situ hybridization, Northern blot analysis on adult and developing mouse tissues\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by in situ hybridization across developmental stages, single lab\",\n      \"pmids\": [\"12088751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM11-deficient mice generated by gene targeting showed deficits in hidden water maze learning and rotating rod motor coordination, while visual water maze performance was normal, indicating that ADAM11 plays a signaling or structural role as a cell adhesion molecule at synapses and participates in synaptic regulation underlying spatial learning and motor coordination.\",\n      \"method\": \"Gene targeting/knockout mouse generation, Morris water maze (visual and hidden tasks), rotating rod behavioral testing, histological analysis\",\n      \"journal\": \"BMC Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific behavioral phenotypes and normal histology; replicated across multiple behavioral paradigms\",\n      \"pmids\": [\"16504143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM11-deficient mice showed reduced responses in the formalin paw test and acetic acid writhing test (models of inflammatory and visceral pain) but normal responses in the von Frey and hot plate tests, indicating ADAM11 plays a role in pain transmission and inflammatory nociception.\",\n      \"method\": \"ADAM11 knockout mice, von Frey test, hot plate test, formalin paw test, acetic acid writhing test\",\n      \"journal\": \"Brain Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with specific phenotypic readouts across multiple pain models, single lab\",\n      \"pmids\": [\"16729981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LGI1 and LGI4 were identified as binding partners of ADAM11 (as well as ADAM22 and ADAM23); binding was demonstrated by immunoprecipitation from mouse brain lysates, mass spectrometric identification, and a quantitative cell-ELISA system, indicating that the LGI-ADAM system involves multiple ADAM receptors and is regulated by cell-type-specific expression.\",\n      \"method\": \"Immunoprecipitation from mouse brain, mass spectrometric analysis, quantitative cell-ELISA binding assay\",\n      \"journal\": \"International Journal of Biological Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal IP from native tissue plus orthogonal quantitative binding assay, moderate evidence\",\n      \"pmids\": [\"18974846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADAM11 was identified as the first Kv1-interacting protein essential for localizing Kv1.1 and Kv1.2 subunit complexes to the cerebellar basket cell pinceau terminal; in Adam11 mutant mice, Kv1 channels were absent from the distal pinceau terminal while perisomatic GABAergic synaptic release was unaffected, and ultrarapid ephaptic inhibitory synchronization of Purkinje cell firing was abolished, demonstrating that ADAM11-anchored presynaptic Kv1 channels mediate ephaptic (electrical) rather than chemical neurotransmission at this synapse.\",\n      \"method\": \"Adam11 mutant mice, immunofluorescence and immunoelectron microscopy for Kv1.1/Kv1.2 localization, electrophysiological recording of spontaneous IPSCs, field potential recording of ephaptic inhibitory responses, ultrastructural analysis\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO with direct localization of specific channel complexes, electrophysiological functional readouts distinguishing chemical vs. ephaptic transmission, multiple orthogonal methods\",\n      \"pmids\": [\"26269648\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM11 is a catalytically inactive (disrupted zinc-binding motif), brain-enriched transmembrane ADAM family protein that functions as a cell adhesion/scaffolding molecule: it serves as a receptor for LGI1 and LGI4 ligands in the nervous system, and is essential for localizing Kv1.1/Kv1.2 potassium channel complexes to the cerebellar basket cell pinceau terminal, where these channels mediate ephaptic (non-synaptic electrical) inhibitory control of Purkinje cell firing; loss of ADAM11 impairs spatial learning, motor coordination, and inflammatory nociception in mice.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAM11 is a catalytically inactive transmembrane disintegrin-metalloprotease family member that functions as an adhesion and scaffolding molecule in the nervous system. Its domain architecture includes metalloprotease-like, disintegrin, cysteine-rich/EGF-like, transmembrane, and cytoplasmic domains, and it is expressed neuron-specifically throughout the CNS and PNS [PMID:7956356, PMID:12088751]. ADAM11 binds the secreted ligands LGI1 and LGI4, placing it within a broader LGI–ADAM signaling network [PMID:18974846], and it is essential for clustering Kv1.1/Kv1.2 potassium channels at cerebellar basket cell pinceau terminals, where its loss abolishes ephaptic inhibition of Purkinje cell firing [PMID:26269648]. ADAM11-deficient mice exhibit deficits in spatial learning, motor coordination, and inflammatory pain transmission, demonstrating its requirement for normal synaptic function in hippocampus, cerebellum, and pain circuits [PMID:16504143, PMID:16729981].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Cloning and structural characterization of ADAM11 established its multi-domain architecture — including a catalytically inactive metalloprotease-like domain, disintegrin domain, and transmembrane segment — defining it as a non-proteolytic ADAM family member and raising the question of its biological function.\",\n      \"evidence\": \"cDNA cloning and exon-intron mapping of the human MDC/ADAM11 gene\",\n      \"pmids\": [\"7956356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data; role of each domain untested\", \"Alternative splice isoform (524 aa) function unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration that ADAM11, along with ADAM22 and ADAM23, is highly and preferentially expressed in the brain established the neural ADAM subfamily and suggested conserved nervous system roles.\",\n      \"evidence\": \"Northern blot analysis and chromosomal mapping in mouse showing synteny with human orthologs\",\n      \"pmids\": [\"10433968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Expression data alone; no loss-of-function or binding studies\", \"Cell-type resolution not provided\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"In situ hybridization resolved ADAM11 expression to neurons specifically — across forebrain, brainstem, cerebellum, spinal cord, and peripheral ganglia — and revealed dynamic developmental regulation, narrowing the functional context to neuron-neuron or neuron-glia interactions.\",\n      \"evidence\": \"In situ hybridization and Northern blot in developing and adult mouse tissues\",\n      \"pmids\": [\"12088751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No protein-level localization (subcellular or synaptic)\", \"No functional perturbation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"ADAM11 knockout mice revealed that the gene is required for spatial learning and motor coordination (hippocampal and cerebellar circuits) and for inflammatory pain transmission, providing the first direct evidence of its physiological necessity.\",\n      \"evidence\": \"Gene-targeted ADAM11-null mice tested by Morris water maze, rotarod, formalin paw, acetic acid writhing, von Frey, and hot plate assays\",\n      \"pmids\": [\"16504143\", \"16729981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic and molecular mechanism underlying behavioral deficits unknown\", \"Downstream signaling pathways uncharacterized\", \"Whether pain phenotype reflects central or peripheral ADAM11 function unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of LGI1 and LGI4 as ADAM11 ligands placed ADAM11 within the LGI–ADAM receptor system, demonstrating that multiple ADAM receptors share LGI ligands and that specificity likely arises from cell-type-restricted expression.\",\n      \"evidence\": \"Immunoprecipitation from mouse brain with mass spectrometry, confirmed by quantitative cell-ELISA binding assays\",\n      \"pmids\": [\"18974846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; binding affinities relative to ADAM22 not fully resolved\", \"Functional consequence of LGI–ADAM11 interaction in vivo untested\", \"Whether LGI binding is required for ADAM11's channel-clustering role unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ADAM11 was identified as the first transmembrane protein essential for Kv1.1/Kv1.2 potassium channel clustering at the cerebellar basket cell pinceau, mechanistically explaining how loss of ADAM11 abolishes ephaptic inhibition of Purkinje cells while leaving GABAergic transmission intact.\",\n      \"evidence\": \"Adam11 mutant mice analyzed by immunofluorescence, electron microscopy, and in vivo electrophysiology of Purkinje cell firing and ephaptic currents\",\n      \"pmids\": [\"26269648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between ADAM11 and Kv1 subunits not demonstrated biochemically\", \"Whether ADAM11 clusters Kv1 channels at other synapses (e.g., hippocampus) unknown\", \"Molecular mechanism of channel anchoring or recruitment not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include whether ADAM11 directly binds Kv1 channel subunits, how LGI ligand binding relates to channel clustering, which cytoplasmic interactors mediate its scaffolding function, and whether its role in pain and learning also involves Kv1 channel regulation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical demonstration of ADAM11–Kv1 physical interaction\", \"Signaling downstream of LGI–ADAM11 engagement uncharacterized\", \"Role of cytoplasmic domain and its binding partners undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LGI1\", \"LGI4\", \"KCNA1\", \"KCNA2\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ADAM11 is a catalytically inactive, brain-enriched member of the ADAM (a disintegrin and metalloproteinase) family that functions as a transmembrane adhesion and scaffolding molecule in the nervous system. Its metalloprotease-like domain lacks a functional zinc-binding motif, and its disintegrin domain lacks the canonical RGD integrin-binding sequence, consistent with non-proteolytic roles in cell–cell interaction [PMID:9693107]. ADAM11 serves as a receptor for the secreted ligands LGI1 and LGI4 [PMID:18974846] and is essential for anchoring Kv1.1/Kv1.2 potassium channel complexes at the cerebellar basket cell pinceau terminal, where these channels mediate ultrarapid ephaptic (non-synaptic electrical) inhibition of Purkinje cell firing [PMID:26269648]. Loss of ADAM11 in mice impairs spatial learning, motor coordination, and inflammatory nociception [PMID:16504143, PMID:16729981].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of ADAM11 as a novel metalloprotease-disintegrin-cysteine-rich gene at 17q21.3 established it as a candidate of interest, initially through somatic rearrangements in breast tumors.\",\n      \"evidence\": \"Genomic cloning from a cosmid library with Southern blot detection of rearrangements in primary breast cancers\",\n      \"pmids\": [\"8252040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tumor-suppressor role never independently validated\", \"No functional assay performed\", \"Only two tumors showed rearrangement\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Sequence analysis resolved that ADAM11 is catalytically inactive due to a disrupted zinc-binding motif and lacks the RGD disintegrin sequence, redirecting its functional interpretation from a protease toward an adhesion/scaffolding molecule.\",\n      \"evidence\": \"cDNA cloning and sequence comparison of metalloprotease and disintegrin domains; Northern blot showing high brain expression\",\n      \"pmids\": [\"9693107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding partners unknown\", \"No functional assay demonstrating adhesion activity\", \"Protein-level expression and localization not determined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Detailed expression mapping revealed ADAM11 mRNA in neurons across the CNS, PNS, and select non-neural tissues during development, narrowing its likely function to neuron–neuron or neuron–glia interactions.\",\n      \"evidence\": \"In situ hybridization and Northern blot across adult and developing mouse tissues\",\n      \"pmids\": [\"12088751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protein localization at subcellular level not addressed\", \"No loss-of-function data yet available\", \"Cell-type-specific roles unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Generation of ADAM11 knockout mice demonstrated that the protein is required for normal spatial learning, motor coordination, and inflammatory nociception, establishing its in vivo physiological importance without overt structural brain abnormalities.\",\n      \"evidence\": \"Gene-targeted knockout mice tested with Morris water maze, rotating rod, formalin paw, and acetic acid writhing assays\",\n      \"pmids\": [\"16504143\", \"16729981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism underlying behavioral deficits unknown\", \"Synaptic partners unidentified\", \"Pain-signaling pathway not delineated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of LGI1 and LGI4 as ligands for ADAM11 established a receptor–ligand system analogous to LGI–ADAM22 interactions, suggesting cell-type-specific signaling through the LGI–ADAM axis.\",\n      \"evidence\": \"Immunoprecipitation from mouse brain lysates, mass spectrometry, and quantitative cell-ELISA binding assays\",\n      \"pmids\": [\"18974846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling events triggered by LGI binding to ADAM11 not characterized\", \"Structural basis of selectivity among ADAM11/22/23 for LGI ligands unknown\", \"In vivo relevance of LGI4–ADAM11 interaction not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ADAM11 was shown to be the critical anchor for Kv1.1/Kv1.2 channel complexes at the basket cell pinceau, and its loss abolished ephaptic inhibition of Purkinje cells while leaving chemical GABAergic transmission intact — defining ADAM11's primary electrophysiological function.\",\n      \"evidence\": \"Adam11 mutant mice analyzed by immunofluorescence, immunoelectron microscopy for Kv1 localization, and electrophysiology distinguishing ephaptic vs. chemical transmission\",\n      \"pmids\": [\"26269648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between ADAM11 and Kv1 subunits not biochemically demonstrated\", \"Whether ADAM11 anchors Kv1 channels at other brain sites is unknown\", \"Relationship between Kv1 anchoring and the spatial learning/nociception phenotypes is unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include whether ADAM11 directly binds Kv1 channels or requires intermediary scaffolding partners, how LGI ligand binding modulates ADAM11's channel-anchoring function, and whether ADAM11 serves analogous scaffolding roles outside the cerebellum.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No biochemical reconstitution of ADAM11–Kv1 complex\", \"Structural basis of ADAM11 function unresolved\", \"Role outside cerebellum and in peripheral nociceptive circuits not mechanistically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LGI1\", \"LGI4\", \"KCNA1\", \"KCNA2\"],\n    \"other_free_text\": []\n  }\n}\n```"}