{"gene":"ADAM11","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":1998,"finding":"ADAM11 (MDC/MDC protein) lacks a functional zinc-binding motif in its metalloproteinase-like domain, indicating it is catalytically inactive and cannot function as a protease. Its disintegrin-like domain lacks the RGD integrin-binding sequence but contains a related loop structure, suggesting a role as an integrin ligand rather than a sheddase.","method":"Sequence analysis and cloning; comparative domain architecture analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — sequence-based structural inference replicated across multiple independent cloning studies (PMID:9693107, PMID:10433968), establishing the non-catalytic nature of ADAM11","pmids":["9693107","10433968"],"is_preprint":false},{"year":2008,"finding":"ADAM11 binds LGI1 and LGI4 in a cell-ELISA binding system, identifying LGI proteins as ligands for ADAM11 (as well as ADAM22 and ADAM23). This binding indicates ADAM11 participates in the LGI-ADAM signaling system in the brain.","method":"Immunoprecipitation, mass spectrometry, quantitative cell-ELISA binding assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP and quantitative cell-ELISA in single lab; binding to ADAM11 was secondary to the main ADAM22 finding","pmids":["18974846"],"is_preprint":false},{"year":2009,"finding":"ADAM11 binds LGI1 but lacks PDZ-interacting sequences, indicating it operates through PSD-95-independent mechanisms in LGI1-related epilepsy signaling.","method":"Brain gene screen for LGI1 interactors; binding assay; sequence analysis of PDZ motifs","journal":"Molecular and cellular neurosciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, binding assay without full characterization of ADAM11-specific interaction mechanism","pmids":["19796686"],"is_preprint":false},{"year":2006,"finding":"ADAM11-deficient mice show deficits in hidden water maze (spatial learning) and rotating rod (motor coordination) tasks but are histologically normal, indicating ADAM11 plays a functional role at the synapse in learning and motor coordination rather than in cell migration or differentiation during development.","method":"Gene targeting (knockout mice); behavioral testing (Morris water maze, rotarod)","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined behavioral phenotypes in multiple tasks, single lab","pmids":["16504143"],"is_preprint":false},{"year":2006,"finding":"ADAM11 has only a minor effect on glioma cell proliferation in vitro, in contrast to ADAM22 which strongly inhibits proliferation via its disintegrin domain. Overexpression of ADAM11 in glioma cells did not significantly suppress growth.","method":"BrdU incorporation immunocytochemistry; overexpression in glioma cells; GST-disintegrin domain fusion protein treatment","journal":"Neurosurgery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method; this is a negative/minor result for ADAM11 specifically","pmids":["16385342"],"is_preprint":false},{"year":2006,"finding":"ADAM11-deficient mice show reduced pain responses in the formalin paw test and acetic acid writhing test (inflammatory/tonic pain models) but normal responses in the von Frey and hot plate tests (acute nociception), indicating ADAM11 plays a role in inflammatory pain transmission rather than acute nociception.","method":"Knockout mice; von Frey test, hot plate test, formalin paw test, acetic acid writhing test","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple behavioral paradigms distinguishing pain modalities, single lab","pmids":["16729981"],"is_preprint":false},{"year":2015,"finding":"ADAM11 is required for the localization of Kv1.1 and Kv1.2 potassium channel subunit complexes to the cerebellar basket cell pinceau terminal. In ADAM11 mutant mice, Kv1 channels are absent from the distal terminal pinceau, eliminating ephaptic (electrical) inhibitory synchronization of Purkinje cell firing while leaving GABAergic synaptic release intact. ADAM11 is thereby identified as the first Kv1-interacting protein essential for presynaptic potassium channel clustering at this specialized axonal terminal.","method":"ADAM11 mutant mice; immunohistochemistry for Kv1.1/Kv1.2 localization; electrophysiology (spontaneous GABA release, ephaptic inhibitory synchronization assays)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal readouts (channel localization, GABA release, electrophysiology), defining a novel molecular mechanism","pmids":["26269648"],"is_preprint":false},{"year":2015,"finding":"ADAM11 is a member of the Caspr2 (CNTNAP2) interaction proteome in brain, co-precipitating with ADAM22, ADAM23, LGI family members, and Kv1 channel subunits, placing ADAM11 in a synaptic protein complex at the node/paranode region.","method":"Interaction proteomics (immunoprecipitation + mass spectrometry) from mouse hippocampus","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry-based interactome from brain tissue, single lab, ADAM11 is one of many identified interactors","pmids":["25707359"],"is_preprint":false},{"year":2017,"finding":"The disintegrin-like domain of ADAM11 selectively supports integrin α4-dependent cell adhesion, demonstrating that the non-catalytic ADAM11 functions as a ligand for integrin α4. This is the first direct demonstration that the disintegrin-like domain of a catalytically inactive ADAM mediates integrin-dependent adhesion.","method":"Cell adhesion assay using recombinant ADAM11 disintegrin domain; integrin α4 blocking antibodies","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell adhesion assay with domain-specific recombinant protein and integrin-blocking antibody controls, single lab","pmids":["28913673"],"is_preprint":false},{"year":2023,"finding":"Adam11 binds proteins of the Wnt and BMP4 signaling pathways (identified by mass spectrometry), positively regulates BMP4 signaling, and negatively regulates β-catenin (Wnt) activity in cranial neural crest cells. Loss of Adam11 in Xenopus results in altered neural tube closure timing and changes in CNC proliferation and migration. In mouse B16 melanoma cells, ADAM11 levels inversely correlate with Wnt activation and directly with BMP4 activation.","method":"Loss- and gain-of-function in Xenopus laevis; mass spectrometry for binding partners; β-catenin reporter assay; BMP4 signaling assay; mouse B16 melanoma cell experiments","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MS, functional signaling assays, in vivo Xenopus, cancer cell line), single lab, replicated in peer-reviewed and preprint versions","pmids":["37766964","37398217"],"is_preprint":false}],"current_model":"ADAM11 is a catalytically inactive transmembrane disintegrin that functions as an adhesion/signaling scaffold: it localizes Kv1.1/Kv1.2 potassium channels to cerebellar basket cell pinceau terminals to enable ephaptic inhibition of Purkinje cell firing; acts as a ligand for integrin α4 via its disintegrin-like domain; binds LGI1 and LGI4 in the brain; participates in a synaptic complex with Caspr2, ADAM22/23, and Kv1 subunits; and modulates Wnt/β-catenin and BMP4 signaling pathways to regulate neural crest cell proliferation and migration, with loss-of-function causing deficits in spatial learning, motor coordination, and inflammatory pain processing."},"narrative":{"mechanistic_narrative":"ADAM11 is a catalytically inactive transmembrane disintegrin that functions as a neuronal adhesion and channel-organizing scaffold rather than a sheddase, lacking a functional zinc-binding motif in its metalloproteinase-like domain and the canonical RGD sequence in its disintegrin-like domain [PMID:9693107, PMID:10433968]. Its principal characterized role is in the cerebellum, where ADAM11 is required to localize Kv1.1/Kv1.2 potassium channel complexes to the basket cell pinceau terminal; in its absence Kv1 channels are lost from the distal terminal, abolishing ephaptic inhibitory synchronization of Purkinje cell firing while sparing GABAergic release, identifying ADAM11 as a Kv1-interacting protein essential for presynaptic channel clustering [PMID:26269648]. Consistent with a synaptic scaffolding function, ADAM11 binds the LGI proteins LGI1 and LGI4 and co-assembles with Caspr2 (CNTNAP2), ADAM22, ADAM23, and Kv1 subunits in a brain synaptic complex [PMID:18974846, PMID:25707359]. Through its disintegrin-like domain ADAM11 also acts as a ligand supporting integrin α4-dependent cell adhesion [PMID:28913673], and it engages Wnt and BMP4 pathway components to positively regulate BMP4 signaling and negatively regulate β-catenin activity during neural crest proliferation and migration [PMID:37766964, PMID:37398217]. Loss of ADAM11 in mice produces deficits in spatial learning and motor coordination and reduced inflammatory pain responses without histological abnormality, indicating a functional synaptic rather than developmental role in the brain [PMID:16504143, PMID:16729981].","teleology":[{"year":1998,"claim":"Established that ADAM11 is not a protease, redirecting attention from sheddase activity to adhesion/ligand functions and framing all later mechanistic work.","evidence":"Sequence and comparative domain architecture analysis of cloned ADAM11","pmids":["9693107","10433968"],"confidence":"Medium","gaps":["Inference is sequence-based, not biochemical demonstration of absent catalysis","Does not establish what the disintegrin domain binds"]},{"year":2006,"claim":"Defined the in vivo phenotype: knockout mice have spatial learning and motor coordination deficits yet normal histology, locating ADAM11 function at the synapse rather than in development.","evidence":"Gene-targeted knockout mice with Morris water maze and rotarod testing","pmids":["16504143"],"confidence":"Medium","gaps":["Behavioral deficits not linked to a molecular mechanism","Single lab"]},{"year":2006,"claim":"Distinguished ADAM11's role in pain processing, showing it is required for inflammatory/tonic pain but not acute nociception.","evidence":"Knockout mice across formalin, acetic acid writhing, von Frey, and hot plate tests","pmids":["16729981"],"confidence":"Medium","gaps":["Molecular basis of the pain phenotype not identified","Anatomical site of action unknown"]},{"year":2006,"claim":"Contrasted ADAM11 with paralog ADAM22, showing ADAM11 has only minor effect on glioma proliferation, arguing its disintegrin domain function is not anti-proliferative.","evidence":"BrdU incorporation and GST-disintegrin domain fusion treatment in glioma cells","pmids":["16385342"],"confidence":"Low","gaps":["Negative/minor result for ADAM11 specifically","Single lab, single method"]},{"year":2008,"claim":"Identified LGI1 and LGI4 as ligands for ADAM11, embedding it in the LGI-ADAM brain signaling system.","evidence":"Immunoprecipitation, mass spectrometry, and quantitative cell-ELISA binding assay","pmids":["18974846"],"confidence":"Medium","gaps":["ADAM11 binding was secondary to the main ADAM22 finding","Functional consequence of LGI binding to ADAM11 not tested"]},{"year":2009,"claim":"Showed ADAM11 binds LGI1 but lacks PDZ-interacting sequences, implying PSD-95-independent signaling in LGI1-related epilepsy.","evidence":"Brain LGI1-interactor screen with binding and PDZ-motif sequence analysis","pmids":["19796686"],"confidence":"Low","gaps":["ADAM11-specific interaction mechanism not fully characterized","Single lab"]},{"year":2015,"claim":"Provided the defining mechanism: ADAM11 is essential for clustering Kv1.1/Kv1.2 channels at the cerebellar pinceau terminal to enable ephaptic inhibition of Purkinje cells.","evidence":"ADAM11 mutant mice with Kv1 immunohistochemistry, GABA release, and ephaptic electrophysiology","pmids":["26269648"],"confidence":"High","gaps":["Direct physical interaction between ADAM11 and Kv1 subunits not biochemically resolved","Recruitment mechanism to the terminal unknown"]},{"year":2015,"claim":"Placed ADAM11 in the Caspr2 synaptic interactome alongside ADAM22/23, LGI proteins, and Kv1 channels, defining its complex membership.","evidence":"Interaction proteomics (IP + mass spectrometry) from mouse hippocampus","pmids":["25707359"],"confidence":"Medium","gaps":["ADAM11 is one of many interactors; direct vs indirect association unresolved","Stoichiometry and architecture of the complex unknown"]},{"year":2017,"claim":"Demonstrated the disintegrin-like domain of catalytically inactive ADAM11 supports integrin α4-dependent adhesion, giving the domain a defined ligand activity.","evidence":"Cell adhesion assay with recombinant ADAM11 disintegrin domain and integrin α4 blocking antibodies","pmids":["28913673"],"confidence":"Medium","gaps":["Physiological context of integrin α4 binding in brain not established","Single lab"]},{"year":2023,"claim":"Extended ADAM11 function beyond the synapse, linking it to Wnt/BMP4 signaling control of neural crest proliferation and migration.","evidence":"Xenopus loss/gain-of-function, mass spectrometry of partners, β-catenin and BMP4 reporter assays, B16 melanoma cells","pmids":["37766964","37398217"],"confidence":"Medium","gaps":["Direct molecular targets within Wnt/BMP4 pathways not pinpointed","Relevance to mammalian neural crest development not confirmed"]},{"year":null,"claim":"How ADAM11 is recruited to specialized axonal terminals and whether it directly contacts Kv1 channels versus acting through LGI/ADAM22-23/Caspr2 partners remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ADAM11 in the synaptic complex","Direct ADAM11-Kv1 binding not biochemically demonstrated","Mechanism connecting adhesion/ligand activity to channel clustering unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9]}],"complexes":["Caspr2 (CNTNAP2) synaptic complex with ADAM22/23, LGI proteins, and Kv1 channels"],"partners":["LGI1","LGI4","CNTNAP2","ADAM22","ADAM23","KCNA1","KCNA2","ITGA4"],"other_free_text":[]}},"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":"22330064","id":"PMC_22330064","title":"Melatonin 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/37398217","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15055,"output_tokens":2474,"usd":0.041138,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9690,"output_tokens":3216,"usd":0.064425,"stage2_stop_reason":"end_turn"},"total_usd":0.105563,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"ADAM11 (MDC/MDC protein) lacks a functional zinc-binding motif in its metalloproteinase-like domain, indicating it is catalytically inactive and cannot function as a protease. Its disintegrin-like domain lacks the RGD integrin-binding sequence but contains a related loop structure, suggesting a role as an integrin ligand rather than a sheddase.\",\n      \"method\": \"Sequence analysis and cloning; comparative domain architecture analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — sequence-based structural inference replicated across multiple independent cloning studies (PMID:9693107, PMID:10433968), establishing the non-catalytic nature of ADAM11\",\n      \"pmids\": [\"9693107\", \"10433968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM11 binds LGI1 and LGI4 in a cell-ELISA binding system, identifying LGI proteins as ligands for ADAM11 (as well as ADAM22 and ADAM23). This binding indicates ADAM11 participates in the LGI-ADAM signaling system in the brain.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, quantitative cell-ELISA binding assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP and quantitative cell-ELISA in single lab; binding to ADAM11 was secondary to the main ADAM22 finding\",\n      \"pmids\": [\"18974846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM11 binds LGI1 but lacks PDZ-interacting sequences, indicating it operates through PSD-95-independent mechanisms in LGI1-related epilepsy signaling.\",\n      \"method\": \"Brain gene screen for LGI1 interactors; binding assay; sequence analysis of PDZ motifs\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, binding assay without full characterization of ADAM11-specific interaction mechanism\",\n      \"pmids\": [\"19796686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM11-deficient mice show deficits in hidden water maze (spatial learning) and rotating rod (motor coordination) tasks but are histologically normal, indicating ADAM11 plays a functional role at the synapse in learning and motor coordination rather than in cell migration or differentiation during development.\",\n      \"method\": \"Gene targeting (knockout mice); behavioral testing (Morris water maze, rotarod)\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined behavioral phenotypes in multiple tasks, single lab\",\n      \"pmids\": [\"16504143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM11 has only a minor effect on glioma cell proliferation in vitro, in contrast to ADAM22 which strongly inhibits proliferation via its disintegrin domain. Overexpression of ADAM11 in glioma cells did not significantly suppress growth.\",\n      \"method\": \"BrdU incorporation immunocytochemistry; overexpression in glioma cells; GST-disintegrin domain fusion protein treatment\",\n      \"journal\": \"Neurosurgery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method; this is a negative/minor result for ADAM11 specifically\",\n      \"pmids\": [\"16385342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM11-deficient mice show reduced pain responses in the formalin paw test and acetic acid writhing test (inflammatory/tonic pain models) but normal responses in the von Frey and hot plate tests (acute nociception), indicating ADAM11 plays a role in inflammatory pain transmission rather than acute nociception.\",\n      \"method\": \"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 / Moderate — clean KO with multiple behavioral paradigms distinguishing pain modalities, single lab\",\n      \"pmids\": [\"16729981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADAM11 is required for the localization of Kv1.1 and Kv1.2 potassium channel subunit complexes to the cerebellar basket cell pinceau terminal. In ADAM11 mutant mice, Kv1 channels are absent from the distal terminal pinceau, eliminating ephaptic (electrical) inhibitory synchronization of Purkinje cell firing while leaving GABAergic synaptic release intact. ADAM11 is thereby identified as the first Kv1-interacting protein essential for presynaptic potassium channel clustering at this specialized axonal terminal.\",\n      \"method\": \"ADAM11 mutant mice; immunohistochemistry for Kv1.1/Kv1.2 localization; electrophysiology (spontaneous GABA release, ephaptic inhibitory synchronization assays)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal readouts (channel localization, GABA release, electrophysiology), defining a novel molecular mechanism\",\n      \"pmids\": [\"26269648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADAM11 is a member of the Caspr2 (CNTNAP2) interaction proteome in brain, co-precipitating with ADAM22, ADAM23, LGI family members, and Kv1 channel subunits, placing ADAM11 in a synaptic protein complex at the node/paranode region.\",\n      \"method\": \"Interaction proteomics (immunoprecipitation + mass spectrometry) from mouse hippocampus\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry-based interactome from brain tissue, single lab, ADAM11 is one of many identified interactors\",\n      \"pmids\": [\"25707359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The disintegrin-like domain of ADAM11 selectively supports integrin α4-dependent cell adhesion, demonstrating that the non-catalytic ADAM11 functions as a ligand for integrin α4. This is the first direct demonstration that the disintegrin-like domain of a catalytically inactive ADAM mediates integrin-dependent adhesion.\",\n      \"method\": \"Cell adhesion assay using recombinant ADAM11 disintegrin domain; integrin α4 blocking antibodies\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell adhesion assay with domain-specific recombinant protein and integrin-blocking antibody controls, single lab\",\n      \"pmids\": [\"28913673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Adam11 binds proteins of the Wnt and BMP4 signaling pathways (identified by mass spectrometry), positively regulates BMP4 signaling, and negatively regulates β-catenin (Wnt) activity in cranial neural crest cells. Loss of Adam11 in Xenopus results in altered neural tube closure timing and changes in CNC proliferation and migration. In mouse B16 melanoma cells, ADAM11 levels inversely correlate with Wnt activation and directly with BMP4 activation.\",\n      \"method\": \"Loss- and gain-of-function in Xenopus laevis; mass spectrometry for binding partners; β-catenin reporter assay; BMP4 signaling assay; mouse B16 melanoma cell experiments\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MS, functional signaling assays, in vivo Xenopus, cancer cell line), single lab, replicated in peer-reviewed and preprint versions\",\n      \"pmids\": [\"37766964\", \"37398217\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM11 is a catalytically inactive transmembrane disintegrin that functions as an adhesion/signaling scaffold: it localizes Kv1.1/Kv1.2 potassium channels to cerebellar basket cell pinceau terminals to enable ephaptic inhibition of Purkinje cell firing; acts as a ligand for integrin α4 via its disintegrin-like domain; binds LGI1 and LGI4 in the brain; participates in a synaptic complex with Caspr2, ADAM22/23, and Kv1 subunits; and modulates Wnt/β-catenin and BMP4 signaling pathways to regulate neural crest cell proliferation and migration, with loss-of-function causing deficits in spatial learning, motor coordination, and inflammatory pain processing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAM11 is a catalytically inactive transmembrane disintegrin that functions as a neuronal adhesion and channel-organizing scaffold rather than a sheddase, lacking a functional zinc-binding motif in its metalloproteinase-like domain and the canonical RGD sequence in its disintegrin-like domain [#0]. Its principal characterized role is in the cerebellum, where ADAM11 is required to localize Kv1.1/Kv1.2 potassium channel complexes to the basket cell pinceau terminal; in its absence Kv1 channels are lost from the distal terminal, abolishing ephaptic inhibitory synchronization of Purkinje cell firing while sparing GABAergic release, identifying ADAM11 as a Kv1-interacting protein essential for presynaptic channel clustering [#6]. Consistent with a synaptic scaffolding function, ADAM11 binds the LGI proteins LGI1 and LGI4 and co-assembles with Caspr2 (CNTNAP2), ADAM22, ADAM23, and Kv1 subunits in a brain synaptic complex [#1, #7]. Through its disintegrin-like domain ADAM11 also acts as a ligand supporting integrin \\u03b14-dependent cell adhesion [#8], and it engages Wnt and BMP4 pathway components to positively regulate BMP4 signaling and negatively regulate \\u03b2-catenin activity during neural crest proliferation and migration [#9]. Loss of ADAM11 in mice produces deficits in spatial learning and motor coordination and reduced inflammatory pain responses without histological abnormality, indicating a functional synaptic rather than developmental role in the brain [#3, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that ADAM11 is not a protease, redirecting attention from sheddase activity to adhesion/ligand functions and framing all later mechanistic work.\",\n      \"evidence\": \"Sequence and comparative domain architecture analysis of cloned ADAM11\",\n      \"pmids\": [\"9693107\", \"10433968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inference is sequence-based, not biochemical demonstration of absent catalysis\", \"Does not establish what the disintegrin domain binds\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the in vivo phenotype: knockout mice have spatial learning and motor coordination deficits yet normal histology, locating ADAM11 function at the synapse rather than in development.\",\n      \"evidence\": \"Gene-targeted knockout mice with Morris water maze and rotarod testing\",\n      \"pmids\": [\"16504143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Behavioral deficits not linked to a molecular mechanism\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Distinguished ADAM11's role in pain processing, showing it is required for inflammatory/tonic pain but not acute nociception.\",\n      \"evidence\": \"Knockout mice across formalin, acetic acid writhing, von Frey, and hot plate tests\",\n      \"pmids\": [\"16729981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the pain phenotype not identified\", \"Anatomical site of action unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Contrasted ADAM11 with paralog ADAM22, showing ADAM11 has only minor effect on glioma proliferation, arguing its disintegrin domain function is not anti-proliferative.\",\n      \"evidence\": \"BrdU incorporation and GST-disintegrin domain fusion treatment in glioma cells\",\n      \"pmids\": [\"16385342\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Negative/minor result for ADAM11 specifically\", \"Single lab, single method\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified LGI1 and LGI4 as ligands for ADAM11, embedding it in the LGI-ADAM brain signaling system.\",\n      \"evidence\": \"Immunoprecipitation, mass spectrometry, and quantitative cell-ELISA binding assay\",\n      \"pmids\": [\"18974846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADAM11 binding was secondary to the main ADAM22 finding\", \"Functional consequence of LGI binding to ADAM11 not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed ADAM11 binds LGI1 but lacks PDZ-interacting sequences, implying PSD-95-independent signaling in LGI1-related epilepsy.\",\n      \"evidence\": \"Brain LGI1-interactor screen with binding and PDZ-motif sequence analysis\",\n      \"pmids\": [\"19796686\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"ADAM11-specific interaction mechanism not fully characterized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the defining mechanism: ADAM11 is essential for clustering Kv1.1/Kv1.2 channels at the cerebellar pinceau terminal to enable ephaptic inhibition of Purkinje cells.\",\n      \"evidence\": \"ADAM11 mutant mice with Kv1 immunohistochemistry, GABA release, and ephaptic electrophysiology\",\n      \"pmids\": [\"26269648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between ADAM11 and Kv1 subunits not biochemically resolved\", \"Recruitment mechanism to the terminal unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed ADAM11 in the Caspr2 synaptic interactome alongside ADAM22/23, LGI proteins, and Kv1 channels, defining its complex membership.\",\n      \"evidence\": \"Interaction proteomics (IP + mass spectrometry) from mouse hippocampus\",\n      \"pmids\": [\"25707359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADAM11 is one of many interactors; direct vs indirect association unresolved\", \"Stoichiometry and architecture of the complex unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated the disintegrin-like domain of catalytically inactive ADAM11 supports integrin \\u03b14-dependent adhesion, giving the domain a defined ligand activity.\",\n      \"evidence\": \"Cell adhesion assay with recombinant ADAM11 disintegrin domain and integrin \\u03b14 blocking antibodies\",\n      \"pmids\": [\"28913673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of integrin \\u03b14 binding in brain not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended ADAM11 function beyond the synapse, linking it to Wnt/BMP4 signaling control of neural crest proliferation and migration.\",\n      \"evidence\": \"Xenopus loss/gain-of-function, mass spectrometry of partners, \\u03b2-catenin and BMP4 reporter assays, B16 melanoma cells\",\n      \"pmids\": [\"37766964\", \"37398217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets within Wnt/BMP4 pathways not pinpointed\", \"Relevance to mammalian neural crest development not confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ADAM11 is recruited to specialized axonal terminals and whether it directly contacts Kv1 channels versus acting through LGI/ADAM22-23/Caspr2 partners remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ADAM11 in the synaptic complex\", \"Direct ADAM11-Kv1 binding not biochemically demonstrated\", \"Mechanism connecting adhesion/ligand activity to channel clustering unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0112316\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"Caspr2 (CNTNAP2) synaptic complex with ADAM22/23, LGI proteins, and Kv1 channels\"\n    ],\n    \"partners\": [\n      \"LGI1\",\n      \"LGI4\",\n      \"CNTNAP2\",\n      \"ADAM22\",\n      \"ADAM23\",\n      \"KCNA1\",\n      \"KCNA2\",\n      \"ITGA4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}