{"gene":"MED11","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1998,"finding":"MED11 (yeast) is a bona fide subunit of the Mediator complex, verified by copurification and co-immunoprecipitation with RNA polymerase II holoenzyme.","method":"Copurification and co-immunoprecipitation with RNA Pol II holoenzyme; peptide sequence determination","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and copurification, single lab, two orthogonal biochemical methods","pmids":["9812975"],"is_preprint":false},{"year":1999,"finding":"MED11 (yeast) is specifically required for MFalpha1 transcriptional activation, demonstrating an activator-specific role distinct from general Mediator subunits like Med6.","method":"Differential display and Northern analysis of mRNAs from wild-type and Mediator mutant yeast cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic loss-of-function with defined transcriptional phenotype, replicated across multiple Mediator subunits in same study","pmids":["9891034"],"is_preprint":false},{"year":2003,"finding":"Mammalian MED11 is a bona fide subunit of the mammalian Mediator complex, with direct pairwise binding partners identified among known mammalian Mediator subunits.","method":"Tandem mass spectrometry of purified Med8-containing fractions; direct biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification plus direct biochemical binding experiments, single lab","pmids":["12584197"],"is_preprint":false},{"year":2008,"finding":"Yeast Med11 (Mediator head subunit) directly interacts with Rad3 (TFIIH subunit) and with head module subunits Med17 and Med22; disruption of the Med11-Rad3 interaction impairs recruitment of TFIIH, TFIIE, and Pol II to preinitiation complexes, and a med11 mutation reduces Pol II CTD serine 5 phosphorylation genome-wide.","method":"In vivo ChIP genome-wide occupancy assays; genetic interaction analysis via mediator mutations; Pol II CTD phosphorylation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP, genetic epistasis, and biochemical phosphorylation assay, multiple orthogonal methods in one study with clear mechanistic conclusions","pmids":["18691966"],"is_preprint":false},{"year":2011,"finding":"Med11/Med22 (yeast) form a conserved four-helix bundle heterodimer with C-terminal extensions that bind the central head subunit Med17; a highly conserved surface patch on the bundle is required for stable transcription pre-initiation complex (PIC) formation on a Pol II promoter both in vitro and in vivo, and this surface may recruit TFIIH.","method":"Structure-function analysis; in vitro transcription PIC formation assay; in vivo assays with mutant yeast strains; sequence conservation analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of PIC formation combined with mutagenesis and in vivo validation, multiple orthogonal methods","pmids":["21498544"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the Mediator head module from S. pombe at 3.4 Å resolution places Med11 within the neck submodule as part of a helical spine; the structure reveals high conservation and flexibility, and functional elements (jaws, central joint) implicated in Pol II and CTD interactions.","method":"X-ray crystallography at 3.4 Å resolution; functional validation of joint domain in transcription in vitro","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — de novo crystal structure with in vitro transcription functional validation, high-resolution structural data","pmids":["23123849"],"is_preprint":false},{"year":2014,"finding":"Human MED11 knockdown significantly impairs HIV-1 replication at a post-integration step, specifically inhibiting transcription of nascent viral mRNA at the transactivation-responsive element and impairing Tat-induced HIV transcription.","method":"siRNA-mediated knockdown; RT-PCR analysis of early HIV transcripts; viral replication assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with specific transcriptional phenotype readout, single lab, single method per endpoint","pmids":["25100719"],"is_preprint":false},{"year":2022,"finding":"A homozygous truncating variant in MED11 (c.325C>T; p.Arg109Ter) causes a lethal neurodegenerative disease; functional studies on patient-derived fibroblasts show disruption of the MED11 C-terminus rather than loss of protein, likely impairing binding to other Mediator subunits; zebrafish med11 knockout recapitulates key clinical phenotypes including neurodegeneration.","method":"Western blot and RT-PCR on patient-derived fibroblasts; CRISPR/Cas9 zebrafish knockout; exome/genome sequencing","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblast biochemistry plus zebrafish KO model, two orthogonal methods, single lab","pmids":["36001086"],"is_preprint":false}],"current_model":"MED11 is an essential subunit of the Mediator head module that forms a conserved four-helix bundle heterodimer with Med22 (as resolved by crystal structure); this heterodimer binds the central head subunit Med17 and its conserved surface patch directly interacts with the TFIIH subunit Rad3 to recruit TFIIH and TFIIE into the preinitiation complex, thereby facilitating Pol II CTD serine 5 phosphorylation and transcriptional activation; disruption of MED11's C-terminus impairs its binding to other Mediator subunits, and in humans causes a lethal neurodegenerative disease."},"narrative":{"mechanistic_narrative":"MED11 is an essential subunit of the Mediator head module that couples transcriptional activator signals to the assembly of the RNA polymerase II preinitiation complex [PMID:9812975, PMID:18691966]. Within the head module, MED11 (Med11) and Med22 form a conserved four-helix bundle heterodimer whose C-terminal extensions bind the central head subunit Med17, anchoring it within the neck submodule of the head [PMID:21498544, PMID:23123849]. A highly conserved surface patch on this bundle directly engages the TFIIH subunit Rad3 and is required for stable PIC formation; disrupting the Med11-Rad3 interaction impairs recruitment of TFIIH, TFIIE, and Pol II, and reduces genome-wide Pol II CTD serine 5 phosphorylation [PMID:18691966, PMID:21498544]. Genetic loss of MED11 produces activator-specific transcriptional defects rather than a global shutdown, consistent with a role in conveying particular activation signals [PMID:9891034]. Human MED11 is required for Tat-dependent transcription of HIV-1 at a post-integration step [PMID:25100719], and a homozygous truncating variant (p.Arg109Ter) that disrupts the MED11 C-terminus causes a lethal neurodegenerative disease, with a zebrafish knockout recapitulating key phenotypes [PMID:36001086].","teleology":[{"year":1998,"claim":"Established that MED11 is a genuine constituent of the Mediator/Pol II holoenzyme rather than a loosely associated factor, defining it as part of the core transcription machinery.","evidence":"Copurification and reciprocal co-immunoprecipitation with Pol II holoenzyme plus peptide sequencing in yeast","pmids":["9812975"],"confidence":"Medium","gaps":["Did not localize MED11 to a specific Mediator module","No functional role assigned"]},{"year":1999,"claim":"Showed that MED11 carries an activator-specific function, distinguishing it from subunits required for general transcription and implying gene-selective regulatory output.","evidence":"Differential display and Northern analysis of Mediator-mutant yeast revealing a specific MFalpha1 activation defect","pmids":["9891034"],"confidence":"Medium","gaps":["Mechanism linking MED11 to specific activators unknown","No direct partner mapping"]},{"year":2003,"claim":"Extended MED11's identity as a bona fide Mediator subunit to mammals and began mapping its direct pairwise contacts within the complex.","evidence":"Tandem mass spectrometry of Med8-containing fractions and direct biochemical binding assays","pmids":["12584197"],"confidence":"Medium","gaps":["Specific binding partners and module assignment not fully resolved","No functional consequence tested in mammals"]},{"year":2008,"claim":"Defined the mechanistic core of MED11 function: a direct head-module contact with the TFIIH subunit Rad3 that drives recruitment of TFIIH, TFIIE, and Pol II and supports CTD serine 5 phosphorylation.","evidence":"Genome-wide ChIP, genetic interaction analysis, and Pol II CTD phosphorylation assays in yeast med11 mutants","pmids":["18691966"],"confidence":"High","gaps":["Structural basis of the Med11-Rad3 interface not resolved here","Whether interaction is direct vs bridged not fully distinguished"]},{"year":2011,"claim":"Resolved the architecture of MED11 as a four-helix bundle heterodimer with Med22 anchored to Med17, and identified a conserved surface patch essential for PIC formation.","evidence":"Structure-function analysis with in vitro PIC reconstitution and in vivo mutant validation in yeast","pmids":["21498544"],"confidence":"High","gaps":["Direct atomic-resolution contact with TFIIH not visualized","Patch's precise recruitment partner inferred, not co-crystallized"]},{"year":2012,"claim":"Placed MED11 in the high-resolution head-module structure within the neck submodule helical spine, contextualizing its position relative to Pol II and CTD-interacting elements.","evidence":"X-ray crystallography of the S. pombe Mediator head at 3.4 Å with in vitro transcription validation","pmids":["23123849"],"confidence":"High","gaps":["Structure is of the isolated head, not the full PIC","Dynamic conformational changes during recruitment not captured"]},{"year":2014,"claim":"Demonstrated a host-factor role for human MED11 in Tat-dependent HIV-1 transcription, extending its Pol II transcription function to a pathogen-relevant context.","evidence":"siRNA knockdown with RT-PCR of early HIV transcripts and viral replication assays in human cells","pmids":["25100719"],"confidence":"Medium","gaps":["Whether effect is direct or via global Mediator function unclear","No mapping of MED11 contacts to the TAR/Tat machinery"]},{"year":2022,"claim":"Linked MED11 to human Mendelian disease, showing that a C-terminal truncation rather than protein loss underlies a lethal neurodegenerative phenotype consistent with impaired Mediator assembly.","evidence":"Patient fibroblast western blot/RT-PCR plus CRISPR zebrafish knockout and exome/genome sequencing","pmids":["36001086"],"confidence":"Medium","gaps":["Direct demonstration of impaired subunit binding for the truncation not shown","Tissue-specific basis of neurodegeneration unexplained"]},{"year":null,"claim":"How MED11's conserved surface patch contacts TFIIH at atomic resolution within an assembled human PIC, and why its disruption produces selective neurodegeneration, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the MED11-TFIIH interface in a complete human PIC","Mechanistic link between truncation and tissue-specific disease unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,3]}],"complexes":["Mediator complex","Mediator head module"],"partners":["MED22","MED17","RAD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P086","full_name":"Mediator of RNA polymerase II transcription subunit 11","aliases":["Mediator complex subunit 11"],"length_aa":117,"mass_kda":13.1,"function":"Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9P086/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MED11","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000161920","cell_line_id":"CID000250","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MED7","stoichiometry":10.0},{"gene":"MED14","stoichiometry":10.0},{"gene":"IXL;MED29","stoichiometry":10.0},{"gene":"MED25","stoichiometry":10.0},{"gene":"MED24","stoichiometry":10.0},{"gene":"MED6","stoichiometry":10.0},{"gene":"MED17","stoichiometry":10.0},{"gene":"MED22","stoichiometry":10.0},{"gene":"MED21","stoichiometry":10.0},{"gene":"MED18","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000250","total_profiled":1310},"omim":[{"mim_id":"620327","title":"NEURODEGENERATION WITH DEVELOPMENTAL DELAY, EARLY RESPIRATORY FAILURE, MYOCLONIC SEIZURES, AND BRAIN ABNORMALITIES; NDDRSB","url":"https://www.omim.org/entry/620327"},{"mim_id":"612385","title":"MEDIATOR COMPLEX SUBUNIT 19; MED19","url":"https://www.omim.org/entry/612385"},{"mim_id":"612384","title":"MEDIATOR COMPLEX SUBUNIT 18; MED18","url":"https://www.omim.org/entry/612384"},{"mim_id":"612383","title":"MEDIATOR COMPLEX SUBUNIT 11; MED11","url":"https://www.omim.org/entry/612383"},{"mim_id":"612382","title":"MEDIATOR COMPLEX SUBUNIT 10; MED10","url":"https://www.omim.org/entry/612382"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED11"},"hgnc":{"alias_symbol":["HSPC296","MGC88387"],"prev_symbol":[]},"alphafold":{"accession":"Q9P086","domains":[{"cath_id":"1.10.287","chopping":"1-81","consensus_level":"medium","plddt":86.1122,"start":1,"end":81},{"cath_id":"1.20.5","chopping":"83-117","consensus_level":"medium","plddt":91.0214,"start":83,"end":117}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P086","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P086-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P086-F1-predicted_aligned_error_v6.png","plddt_mean":87.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED11","jax_strain_url":"https://www.jax.org/strain/search?query=MED11"},"sequence":{"accession":"Q9P086","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P086.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P086/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P086"}},"corpus_meta":[{"pmid":"18691966","id":"PMC_18691966","title":"Mediator-dependent recruitment of TFIIH modules in preinitiation complex.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18691966","citation_count":126,"is_preprint":false},{"pmid":"23123849","id":"PMC_23123849","title":"Structure of the Mediator head module.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23123849","citation_count":88,"is_preprint":false},{"pmid":"9891034","id":"PMC_9891034","title":"Activator-specific requirement of yeast mediator proteins for RNA polymerase II transcriptional activation.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9891034","citation_count":73,"is_preprint":false},{"pmid":"12584197","id":"PMC_12584197","title":"Identification of mammalian Mediator subunits with similarities to yeast Mediator subunits Srb5, Srb6, Med11, and Rox3.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12584197","citation_count":48,"is_preprint":false},{"pmid":"9812975","id":"PMC_9812975","title":"Identification of new mediator subunits in the RNA polymerase II holoenzyme from Saccharomyces cerevisiae.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9812975","citation_count":48,"is_preprint":false},{"pmid":"21498544","id":"PMC_21498544","title":"Mediator head subcomplex Med11/22 contains a common helix bundle building block with a specific function in transcription initiation complex stabilization.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21498544","citation_count":38,"is_preprint":false},{"pmid":"25100719","id":"PMC_25100719","title":"Characterization of the influence of mediator complex in HIV-1 transcription.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25100719","citation_count":28,"is_preprint":false},{"pmid":"33746938","id":"PMC_33746938","title":"Differential Requirements for Mediator Complex Subunits in Drosophila melanogaster Host Defense Against Fungal and Bacterial Pathogens.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33746938","citation_count":19,"is_preprint":false},{"pmid":"36001086","id":"PMC_36001086","title":"A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.","date":"2022","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36001086","citation_count":16,"is_preprint":false},{"pmid":"24952135","id":"PMC_24952135","title":"RNA-Seq for the identification of novel Mediator transcripts in endothelial progenitor cells.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24952135","citation_count":10,"is_preprint":false},{"pmid":"39471666","id":"PMC_39471666","title":"Exercise in ozone-polluted air evokes pathological cardiac hypertrophy via up-regulation of nuclear lncRNA EYA4-au1 and recruiting Med11 to activating EYA4/p27kip1/CK2α/HDAC2 cascade.","date":"2024","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/39471666","citation_count":4,"is_preprint":false},{"pmid":"39578696","id":"PMC_39578696","title":"Prenatal Phenotypic Expansion: A Fetus With Neurodegeneration With Developmental Delay, Early Respiratory Failure, Myoclonic Seizures, and Brain Abnormalities (NDDRSB) and MED11 Variants.","date":"2024","source":"Prenatal diagnosis","url":"https://pubmed.ncbi.nlm.nih.gov/39578696","citation_count":1,"is_preprint":false},{"pmid":"41465117","id":"PMC_41465117","title":"Genetic, Clinical and Neuroradiological Spectrum of MED-Related Disorders: An Updated Review.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41465117","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8603,"output_tokens":1847,"usd":0.026757,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8738,"output_tokens":2547,"usd":0.053683,"stage2_stop_reason":"end_turn"},"total_usd":0.08044,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"MED11 (yeast) is a bona fide subunit of the Mediator complex, verified by copurification and co-immunoprecipitation with RNA polymerase II holoenzyme.\",\n      \"method\": \"Copurification and co-immunoprecipitation with RNA Pol II holoenzyme; peptide sequence determination\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and copurification, single lab, two orthogonal biochemical methods\",\n      \"pmids\": [\"9812975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MED11 (yeast) is specifically required for MFalpha1 transcriptional activation, demonstrating an activator-specific role distinct from general Mediator subunits like Med6.\",\n      \"method\": \"Differential display and Northern analysis of mRNAs from wild-type and Mediator mutant yeast cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic loss-of-function with defined transcriptional phenotype, replicated across multiple Mediator subunits in same study\",\n      \"pmids\": [\"9891034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mammalian MED11 is a bona fide subunit of the mammalian Mediator complex, with direct pairwise binding partners identified among known mammalian Mediator subunits.\",\n      \"method\": \"Tandem mass spectrometry of purified Med8-containing fractions; direct biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification plus direct biochemical binding experiments, single lab\",\n      \"pmids\": [\"12584197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast Med11 (Mediator head subunit) directly interacts with Rad3 (TFIIH subunit) and with head module subunits Med17 and Med22; disruption of the Med11-Rad3 interaction impairs recruitment of TFIIH, TFIIE, and Pol II to preinitiation complexes, and a med11 mutation reduces Pol II CTD serine 5 phosphorylation genome-wide.\",\n      \"method\": \"In vivo ChIP genome-wide occupancy assays; genetic interaction analysis via mediator mutations; Pol II CTD phosphorylation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP, genetic epistasis, and biochemical phosphorylation assay, multiple orthogonal methods in one study with clear mechanistic conclusions\",\n      \"pmids\": [\"18691966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Med11/Med22 (yeast) form a conserved four-helix bundle heterodimer with C-terminal extensions that bind the central head subunit Med17; a highly conserved surface patch on the bundle is required for stable transcription pre-initiation complex (PIC) formation on a Pol II promoter both in vitro and in vivo, and this surface may recruit TFIIH.\",\n      \"method\": \"Structure-function analysis; in vitro transcription PIC formation assay; in vivo assays with mutant yeast strains; sequence conservation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of PIC formation combined with mutagenesis and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"21498544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the Mediator head module from S. pombe at 3.4 Å resolution places Med11 within the neck submodule as part of a helical spine; the structure reveals high conservation and flexibility, and functional elements (jaws, central joint) implicated in Pol II and CTD interactions.\",\n      \"method\": \"X-ray crystallography at 3.4 Å resolution; functional validation of joint domain in transcription in vitro\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — de novo crystal structure with in vitro transcription functional validation, high-resolution structural data\",\n      \"pmids\": [\"23123849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human MED11 knockdown significantly impairs HIV-1 replication at a post-integration step, specifically inhibiting transcription of nascent viral mRNA at the transactivation-responsive element and impairing Tat-induced HIV transcription.\",\n      \"method\": \"siRNA-mediated knockdown; RT-PCR analysis of early HIV transcripts; viral replication assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with specific transcriptional phenotype readout, single lab, single method per endpoint\",\n      \"pmids\": [\"25100719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous truncating variant in MED11 (c.325C>T; p.Arg109Ter) causes a lethal neurodegenerative disease; functional studies on patient-derived fibroblasts show disruption of the MED11 C-terminus rather than loss of protein, likely impairing binding to other Mediator subunits; zebrafish med11 knockout recapitulates key clinical phenotypes including neurodegeneration.\",\n      \"method\": \"Western blot and RT-PCR on patient-derived fibroblasts; CRISPR/Cas9 zebrafish knockout; exome/genome sequencing\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblast biochemistry plus zebrafish KO model, two orthogonal methods, single lab\",\n      \"pmids\": [\"36001086\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED11 is an essential subunit of the Mediator head module that forms a conserved four-helix bundle heterodimer with Med22 (as resolved by crystal structure); this heterodimer binds the central head subunit Med17 and its conserved surface patch directly interacts with the TFIIH subunit Rad3 to recruit TFIIH and TFIIE into the preinitiation complex, thereby facilitating Pol II CTD serine 5 phosphorylation and transcriptional activation; disruption of MED11's C-terminus impairs its binding to other Mediator subunits, and in humans causes a lethal neurodegenerative disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED11 is an essential subunit of the Mediator head module that couples transcriptional activator signals to the assembly of the RNA polymerase II preinitiation complex [#0, #3]. Within the head module, MED11 (Med11) and Med22 form a conserved four-helix bundle heterodimer whose C-terminal extensions bind the central head subunit Med17, anchoring it within the neck submodule of the head [#4, #5]. A highly conserved surface patch on this bundle directly engages the TFIIH subunit Rad3 and is required for stable PIC formation; disrupting the Med11-Rad3 interaction impairs recruitment of TFIIH, TFIIE, and Pol II, and reduces genome-wide Pol II CTD serine 5 phosphorylation [#3, #4]. Genetic loss of MED11 produces activator-specific transcriptional defects rather than a global shutdown, consistent with a role in conveying particular activation signals [#1]. Human MED11 is required for Tat-dependent transcription of HIV-1 at a post-integration step [#6], and a homozygous truncating variant (p.Arg109Ter) that disrupts the MED11 C-terminus causes a lethal neurodegenerative disease, with a zebrafish knockout recapitulating key phenotypes [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that MED11 is a genuine constituent of the Mediator/Pol II holoenzyme rather than a loosely associated factor, defining it as part of the core transcription machinery.\",\n      \"evidence\": \"Copurification and reciprocal co-immunoprecipitation with Pol II holoenzyme plus peptide sequencing in yeast\",\n      \"pmids\": [\"9812975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not localize MED11 to a specific Mediator module\", \"No functional role assigned\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed that MED11 carries an activator-specific function, distinguishing it from subunits required for general transcription and implying gene-selective regulatory output.\",\n      \"evidence\": \"Differential display and Northern analysis of Mediator-mutant yeast revealing a specific MFalpha1 activation defect\",\n      \"pmids\": [\"9891034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking MED11 to specific activators unknown\", \"No direct partner mapping\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended MED11's identity as a bona fide Mediator subunit to mammals and began mapping its direct pairwise contacts within the complex.\",\n      \"evidence\": \"Tandem mass spectrometry of Med8-containing fractions and direct biochemical binding assays\",\n      \"pmids\": [\"12584197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific binding partners and module assignment not fully resolved\", \"No functional consequence tested in mammals\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the mechanistic core of MED11 function: a direct head-module contact with the TFIIH subunit Rad3 that drives recruitment of TFIIH, TFIIE, and Pol II and supports CTD serine 5 phosphorylation.\",\n      \"evidence\": \"Genome-wide ChIP, genetic interaction analysis, and Pol II CTD phosphorylation assays in yeast med11 mutants\",\n      \"pmids\": [\"18691966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Med11-Rad3 interface not resolved here\", \"Whether interaction is direct vs bridged not fully distinguished\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the architecture of MED11 as a four-helix bundle heterodimer with Med22 anchored to Med17, and identified a conserved surface patch essential for PIC formation.\",\n      \"evidence\": \"Structure-function analysis with in vitro PIC reconstitution and in vivo mutant validation in yeast\",\n      \"pmids\": [\"21498544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct atomic-resolution contact with TFIIH not visualized\", \"Patch's precise recruitment partner inferred, not co-crystallized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed MED11 in the high-resolution head-module structure within the neck submodule helical spine, contextualizing its position relative to Pol II and CTD-interacting elements.\",\n      \"evidence\": \"X-ray crystallography of the S. pombe Mediator head at 3.4 Å with in vitro transcription validation\",\n      \"pmids\": [\"23123849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure is of the isolated head, not the full PIC\", \"Dynamic conformational changes during recruitment not captured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a host-factor role for human MED11 in Tat-dependent HIV-1 transcription, extending its Pol II transcription function to a pathogen-relevant context.\",\n      \"evidence\": \"siRNA knockdown with RT-PCR of early HIV transcripts and viral replication assays in human cells\",\n      \"pmids\": [\"25100719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effect is direct or via global Mediator function unclear\", \"No mapping of MED11 contacts to the TAR/Tat machinery\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked MED11 to human Mendelian disease, showing that a C-terminal truncation rather than protein loss underlies a lethal neurodegenerative phenotype consistent with impaired Mediator assembly.\",\n      \"evidence\": \"Patient fibroblast western blot/RT-PCR plus CRISPR zebrafish knockout and exome/genome sequencing\",\n      \"pmids\": [\"36001086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of impaired subunit binding for the truncation not shown\", \"Tissue-specific basis of neurodegeneration unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MED11's conserved surface patch contacts TFIIH at atomic resolution within an assembled human PIC, and why its disruption produces selective neurodegeneration, remain unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the MED11-TFIIH interface in a complete human PIC\", \"Mechanistic link between truncation and tissue-specific disease unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\"Mediator complex\", \"Mediator head module\"],\n    \"partners\": [\"MED22\", \"MED17\", \"RAD3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}