{"gene":"PSMD7","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2014,"finding":"Crystal structure of the S. cerevisiae Rpn11-Rpn8 (PSMD14-PSMD7) MPN-domain heterodimer solved at 2.0 Å resolution. Rpn8 forms two distinct interfaces with Rpn11. Structural and mutational analyses revealed that Rpn11 lacks a conserved surface for ubiquitin Ile44-patch binding, does not contact the proximal ubiquitin moiety, and shows no ubiquitin-linkage specificity, explaining its function as a promiscuous co-translational deubiquitinase during proteasomal substrate processing.","method":"X-ray crystallography (2.0 Å), site-directed mutagenesis, biochemical deubiquitinase assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with mutational and enzymatic validation in a single rigorous study","pmids":["24463465"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the Rpn8-Rpn11 (PSMD7-PSMD14) MPN heterodimer solved using a nanobody-stabilized fusion protein. Full deubiquitylation activity requires incorporation into the 26S proteasome and is coupled to ATP hydrolysis. Activation is normally suppressed by low intrinsic ubiquitin affinity, an insertion segment blocking the substrate access channel, and a conformationally unstable catalytic loop in Rpn11. Docking into proteasome EM density shows Rpn11 contacts ATPase subunits that stabilize the active conformation.","method":"X-ray crystallography, nanobody co-crystallization, in vitro deubiquitylation assay, EM density docking","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional biochemical validation, replicates findings of PMID 24463465 with orthogonal methods","pmids":["24516147"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the human PSMD7/Mov34 MPN domain (residues 1–186) solved at 1.96 Å reveals a dimeric architecture via domain swapping. The MPN domain lacks the conserved zinc-coordinating residues present in catalytically active MPN proteins (Rpn11, Csn5), explaining why PSMD7 has no intrinsic isopeptidase activity; the MPN domain therefore serves a structural rather than catalytic role.","method":"X-ray crystallography (1.96 Å and 3.0 Å), size-exclusion chromatography, dynamic light scattering","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with solution biophysical validation confirming dimer; single lab but multiple orthogonal methods","pmids":["17559875"],"is_preprint":false},{"year":2006,"finding":"The N-terminal eight residues (1–8) of human PSMD7/Mov34 MPN domain are required for proper folding and thermal stability of the domain; truncation mutants lacking residues 1–8 show reduced alpha-helical content and lower expression levels.","method":"Protease resistance assay, circular dichroism spectroscopy, thermal stability measurements","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biophysical characterization in single lab with multiple methods but no functional rescue experiment","pmids":["16842755"],"is_preprint":false},{"year":1995,"finding":"PSMD7 (p40) was identified and cloned as a regulatory subunit of the human 26S proteasome. The protein contains a C-terminal KEKE motif (alternating Lys/Glu residues) and is homologous to the mouse Mov-34 gene product, establishing it as a novel essential regulatory subunit of the 26S proteasome.","method":"cDNA cloning, sequence analysis, biochemical characterization of 26S proteasome subunit composition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical identification as proteasome subunit; foundational cloning and characterization paper","pmids":["7755639"],"is_preprint":false},{"year":1998,"finding":"HIV-1 Vpr directly interacts with hVIP/MOV34 (PSMD7) both in vitro (GST pulldown) and in vivo (co-immunoprecipitation). Vpr-induced cell cycle arrest at G2/M correlates with a change in PSMD7 subcellular localization from nuclear to perinuclear, accompanied by inhibition of maturation-promoting factor (MPF)-associated histone H1 kinase activity.","method":"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, subcellular localization imaging, histone H1 kinase assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction assays plus functional localization shift linked to cell cycle phenotype, single lab","pmids":["9520381"],"is_preprint":false},{"year":2002,"finding":"The carboxyl-terminal domain of hVIP/MOV34 (PSMD7) is required for its interaction with HIV-1 Vpr. In the absence of Vpr, full-length PSMD7 is cytoplasmic; expression of Vpr shifts PSMD7 to a nuclear localization. C-terminal deletion mutants do not respond to Vpr or to dexamethasone, indicating that this domain also mediates glucocorticoid receptor-dependent nucleocytoplasmic shuttling of PSMD7.","method":"Deletion mutant mapping, co-immunoprecipitation, subcellular localization imaging, glucocorticoid receptor signaling assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with multiple deletion mutants plus localization and signaling functional readouts, single lab","pmids":["12237292"],"is_preprint":false},{"year":2016,"finding":"In S. cerevisiae, the C-terminal 30 amino acids of Rpn8 (PSMD7 ortholog) are sufficient for binding to the C terminus of Pih1 (R2TP complex scaffold). This direct interaction mediates ubiquitin-independent proteasomal degradation of Pih1; truncation of the Rpn8 C-terminal disordered region does not affect proteasome assembly but specifically blocks Pih1 degradation both in vivo and in vitro.","method":"Co-immunoprecipitation, truncation mutant analysis, in vitro and in vivo degradation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding domain mapped, in vitro degradation assay performed, single lab with two complementary approaches","pmids":["27053109"],"is_preprint":false},{"year":2021,"finding":"PSMD7 deubiquitinase activity stabilizes RAD23B protein in gastric cancer cells. PSMD7 co-immunoprecipitates with RAD23B, and PSMD7 knockdown enhances RAD23B ubiquitination and degradation, reducing XPC levels and impairing DNA damage repair.","method":"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown with protein stability measurement, xenograft mouse model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed by Co-IP, ubiquitination status measured, functional rescue experiment, single lab","pmids":["34512150"],"is_preprint":false},{"year":2024,"finding":"PSMD7 deubiquitinates and stabilizes SOX2 protein in pancreatic cancer cells, thereby activating Notch1 signaling. Restoration of SOX2 expression rescued the anti-tumor effects of PSMD7 knockdown, placing PSMD7 upstream of SOX2 in the Notch1 pathway.","method":"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function experiments in vitro and in vivo, epistasis rescue experiment","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and ubiquitination assay with epistasis rescue, single lab","pmids":["38494478"],"is_preprint":false},{"year":2023,"finding":"PSMD7 interacts with RAB1A and reduces its ubiquitination, stabilizing RAB1A protein post-translationally in bladder cancer cells. RAB1A functions as a downstream effector of PSMD7 in promoting bladder cancer progression.","method":"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, overexpression rescue experiment","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with ubiquitination assay, single lab, limited mechanistic follow-up","pmids":["38040402"],"is_preprint":false},{"year":2020,"finding":"PSMD7 knockdown in breast cancer cells promotes ubiquitin-dependent degradation of p21 and p27, leading to G0/G1 cell cycle arrest, senescence, and apoptosis, indicating that PSMD7 normally stabilizes these cell cycle inhibitors.","method":"shRNA knockdown, cell cycle analysis, protein stability assay","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect evidence of substrate stabilization from KD phenotype, no direct ubiquitination or interaction assay reported","pmids":["33042429"],"is_preprint":false},{"year":2021,"finding":"PSMD7 knockdown in non-small cell lung cancer cells increases p53 protein levels and induces p21 and PUMA expression in a p53-dependent manner, indicating PSMD7 normally promotes p53 degradation via the proteasome.","method":"shRNA knockdown, western blot, xenograft mouse model","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect pathway placement via KD phenotype, no direct ubiquitination or Co-IP assay reported for p53","pmids":["34234864"],"is_preprint":false},{"year":2018,"finding":"PSMD7 knockdown in esophageal squamous cell carcinoma reduces proteasomal function and suppresses mTOR/p70S6K pathway activity; conversely, PSMD7 overexpression increases phosphorylation of mTOR (Ser2448) and p70S6K (Thr421/Ser424), placing PSMD7 upstream of this pathway.","method":"shRNA knockdown, lentiviral overexpression, western blot for pathway phosphorylation, xenograft mouse model","journal":"FEBS open bio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological pathway readout without direct substrate or interaction assay, single lab","pmids":["29632807"],"is_preprint":false},{"year":2000,"finding":"Murine Mov34 (PSMD7 ortholog) binds the 3'-stem-loop structure of the Japanese encephalitis virus (JEV) 3'-noncoding region RNA, as detected by UV crosslinking, Northwestern blotting, and competition with viral genomic RNA.","method":"Gel retardation assay, UV crosslinking, Northwestern blotting, cDNA library screen, competition RNA binding assay","journal":"Journal of virology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — direct RNA-binding demonstrated biochemically but functional consequence for proteasome biology not established; single lab","pmids":["10799585"],"is_preprint":false}],"current_model":"PSMD7 (Rpn8/MOV34) is a non-catalytic MPN-domain subunit of the 26S proteasome 19S regulatory particle that forms an obligate heterodimer with the deubiquitinase Rpn11/PSMD14 via two conserved interfaces; this heterodimer is required for proteasome lid assembly and for positioning Rpn11 at the ATPase ring entrance where, upon ATP hydrolysis, ubiquitin chains are removed from translocating substrates in a linkage-nonspecific, co-translational manner, while PSMD7's own MPN domain lacks the conserved JAMM zinc-coordination motif and therefore contributes a structural rather than catalytic function; outside the proteasome, PSMD7 also stabilizes specific substrates (RAD23B, SOX2, RAB1A) by reducing their ubiquitination, interacts with HIV-1 Vpr through its C-terminal domain triggering nucleocytoplasmic redistribution, and mediates ubiquitin-independent degradation of certain proteins (e.g., Pih1) through a direct interaction with its C-terminal disordered region."},"narrative":{"mechanistic_narrative":"PSMD7 (Rpn8/Mov34) is a non-catalytic MPN-domain subunit of the 26S proteasome 19S regulatory particle that was originally cloned as the human p40 regulatory subunit homologous to mouse Mov-34 [PMID:7755639]. Its defining mechanistic role is to form an obligate heterodimer with the deubiquitinase Rpn11/PSMD14 through two distinct MPN-MPN interfaces, an arrangement resolved by high-resolution crystal structures of the heterodimer [PMID:24463465, PMID:24516147]. Although both partners carry MPN domains, the PSMD7 domain lacks the conserved zinc-coordinating residues of catalytically active MPN proteins and therefore contributes structural support rather than isopeptidase activity, with its N-terminal residues required for proper folding and stability [PMID:17559875, PMID:16842755]. Full deubiquitylation by the heterodimer is achieved only upon incorporation into the 26S proteasome and is coupled to ATP hydrolysis, with Rpn11 positioned at the ATPase ring where it removes ubiquitin chains from translocating substrates in a linkage-nonspecific manner [PMID:24463465, PMID:24516147]. Beyond its core proteasomal function, PSMD7 acts on specific clients: its C-terminal disordered region directly binds and mediates ubiquitin-independent degradation of Pih1 [PMID:27053109], and in cancer cells PSMD7 reduces ubiquitination to stabilize substrates including RAD23B and SOX2 [PMID:34512150, PMID:38494478]. PSMD7 is also a target of HIV-1 Vpr, which binds its C-terminal domain and triggers a shift in PSMD7 nucleocytoplasmic distribution linked to G2/M cell cycle arrest [PMID:9520381, PMID:12237292].","teleology":[{"year":1995,"claim":"Established the molecular identity of PSMD7 by cloning it as a regulatory subunit of the human 26S proteasome, anchoring all later mechanistic work to a defined proteasome component.","evidence":"cDNA cloning and biochemical analysis of 26S proteasome subunit composition","pmids":["7755639"],"confidence":"Medium","gaps":["Did not resolve the subunit's structural role or catalytic status","No interaction partners within the proteasome defined"]},{"year":1998,"claim":"Showed PSMD7 is a direct target of HIV-1 Vpr, connecting a proteasome subunit to viral manipulation of the cell cycle.","evidence":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, and histone H1 kinase assay linking Vpr binding to G2/M arrest","pmids":["9520381"],"confidence":"Medium","gaps":["Binding region on PSMD7 not yet mapped","Mechanistic link between localization shift and MPF inhibition not resolved"]},{"year":2000,"claim":"Tested whether PSMD7 has RNA-binding capacity, identifying direct binding to the JEV 3' noncoding RNA stem-loop.","evidence":"UV crosslinking, Northwestern blotting, and competition RNA-binding assays with murine Mov34","pmids":["10799585"],"confidence":"Low","gaps":["Functional consequence for proteasome biology not established","Single lab, no in vivo validation"]},{"year":2002,"claim":"Mapped the Vpr-binding and shuttling determinant to the PSMD7 C-terminal domain, explaining how Vpr and glucocorticoid signaling redirect PSMD7 localization.","evidence":"Deletion mutant mapping with co-IP, localization imaging, and glucocorticoid receptor signaling assays","pmids":["12237292"],"confidence":"Medium","gaps":["Cellular consequence of nuclear redistribution incompletely defined","Single lab"]},{"year":2007,"claim":"Determined the human PSMD7 MPN domain structure and demonstrated it lacks the catalytic zinc-coordination motif, establishing it as a non-catalytic structural subunit.","evidence":"X-ray crystallography (1.96 Å) with size-exclusion chromatography and dynamic light scattering","pmids":["17559875"],"confidence":"High","gaps":["Domain-swapped dimer biological relevance versus heterodimer not resolved","No proteasome-context structure"]},{"year":2014,"claim":"Resolved the Rpn11-Rpn8 (PSMD14-PSMD7) heterodimer at atomic resolution and explained why the deubiquitinase is promiscuous and ATP-coupled, defining the core mechanism of co-translational chain removal.","evidence":"Two independent crystal structures (2.0 Å; nanobody-stabilized) with mutagenesis, in vitro deubiquitylation assays, and EM density docking","pmids":["24463465","24516147"],"confidence":"High","gaps":["PSMD7's specific contribution to lid assembly not separately dissected","Dynamics of activation upon proteasome incorporation not fully captured"]},{"year":2016,"claim":"Demonstrated a proteasome-assembly-independent role for the PSMD7 C-terminus in mediating ubiquitin-independent degradation of Pih1, revealing a substrate-recruitment function distinct from the catalytic heterodimer.","evidence":"Truncation mapping with in vitro and in vivo degradation assays in S. cerevisiae","pmids":["27053109"],"confidence":"Medium","gaps":["Generality of ubiquitin-independent recruitment to other substrates unknown","Structural basis of disordered-region binding not resolved"]},{"year":2021,"claim":"Showed PSMD7 stabilizes RAD23B by reducing its ubiquitination, linking PSMD7 to DNA damage repair via XPC in cancer cells.","evidence":"Co-IP, ubiquitination assay, shRNA knockdown with stability measurement, and xenograft model","pmids":["34512150"],"confidence":"Medium","gaps":["Whether stabilization is direct deubiquitination by PSMD7 versus indirect not distinguished","Single lab"]},{"year":2024,"claim":"Extended the substrate-stabilization role to SOX2, placing PSMD7 upstream of Notch1 signaling through deubiquitination-dependent SOX2 stabilization.","evidence":"Co-IP, ubiquitination assay, and epistasis rescue in pancreatic cancer cells in vitro and in vivo","pmids":["38494478"],"confidence":"Medium","gaps":["Direct catalytic mechanism for an MPN domain lacking the JAMM motif not reconciled","Single lab"]},{"year":null,"claim":"How PSMD7, whose MPN domain lacks catalytic residues, mediates substrate-specific stabilization and ubiquitin-independent degradation outside the Rpn11 heterodimer remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural basis for substrate-specific client binding outside the proteasome","Unclear whether reported deubiquitination of clients is intrinsic or relies on associated DUBs","Relationship between proteasomal and extra-proteasomal pools undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,8,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,4]}],"complexes":["26S proteasome 19S regulatory particle"],"partners":["PSMD14","VPR","RAD23B","SOX2","RAB1A","PIH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51665","full_name":"26S proteasome non-ATPase regulatory subunit 7","aliases":["26S proteasome regulatory subunit RPN8","26S proteasome regulatory subunit S12","Mov34 protein homolog","Proteasome subunit p40"],"length_aa":324,"mass_kda":37.0,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P51665/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD7","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000103035","cell_line_id":"CID000120","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"big_aggregates","grade":2},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"PSMC4","stoichiometry":10.0},{"gene":"PSMC6","stoichiometry":10.0},{"gene":"PSMD12","stoichiometry":10.0},{"gene":"PSMD2","stoichiometry":10.0},{"gene":"PSMC1","stoichiometry":10.0},{"gene":"PSMC5","stoichiometry":10.0},{"gene":"PSMD6","stoichiometry":10.0},{"gene":"PSMD13","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0},{"gene":"PSMD1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000120","total_profiled":1310},"omim":[{"mim_id":"614729","title":"COP9 SIGNALOSOME, SUBUNIT 6; COPS6","url":"https://www.omim.org/entry/614729"},{"mim_id":"607173","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 14; PSMD14","url":"https://www.omim.org/entry/607173"},{"mim_id":"604850","title":"COP9 SIGNALOSOME, SUBUNIT 5; COPS5","url":"https://www.omim.org/entry/604850"},{"mim_id":"157970","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 7; PSMD7","url":"https://www.omim.org/entry/157970"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Acrosome","reliability":"Approved"},{"location":"Equatorial segment","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMD7"},"hgnc":{"alias_symbol":["S12","P40","MOV34","Rpn8"],"prev_symbol":[]},"alphafold":{"accession":"P51665","domains":[{"cath_id":"3.40.140.10","chopping":"7-180","consensus_level":"high","plddt":85.8417,"start":7,"end":180},{"cath_id":"1.20.5","chopping":"184-237","consensus_level":"medium","plddt":85.8972,"start":184,"end":237},{"cath_id":"1.20.5","chopping":"240-291","consensus_level":"medium","plddt":89.2463,"start":240,"end":291}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51665","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51665-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51665-F1-predicted_aligned_error_v6.png","plddt_mean":83.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD7","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD7"},"sequence":{"accession":"P51665","fasta_url":"https://rest.uniprot.org/uniprotkb/P51665.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51665/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51665"}},"corpus_meta":[{"pmid":"24463465","id":"PMC_24463465","title":"Structure of the Rpn11-Rpn8 dimer reveals mechanisms of substrate deubiquitination during proteasomal degradation.","date":"2014","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24463465","citation_count":133,"is_preprint":false},{"pmid":"24516147","id":"PMC_24516147","title":"Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24516147","citation_count":114,"is_preprint":false},{"pmid":"9520381","id":"PMC_9520381","title":"HIV-1 Vpr interacts with a human 34-kDa mov34 homologue, a cellular factor linked to the G2/M phase transition of the mammalian cell cycle.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of 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GlRpn11","date":"2024-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.18.613619","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13007,"output_tokens":3737,"usd":0.047538,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11497,"output_tokens":3098,"usd":0.067467,"stage2_stop_reason":"end_turn"},"total_usd":0.115005,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the S. cerevisiae Rpn11-Rpn8 (PSMD14-PSMD7) MPN-domain heterodimer solved at 2.0 Å resolution. Rpn8 forms two distinct interfaces with Rpn11. Structural and mutational analyses revealed that Rpn11 lacks a conserved surface for ubiquitin Ile44-patch binding, does not contact the proximal ubiquitin moiety, and shows no ubiquitin-linkage specificity, explaining its function as a promiscuous co-translational deubiquitinase during proteasomal substrate processing.\",\n      \"method\": \"X-ray crystallography (2.0 Å), site-directed mutagenesis, biochemical deubiquitinase assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with mutational and enzymatic validation in a single rigorous study\",\n      \"pmids\": [\"24463465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the Rpn8-Rpn11 (PSMD7-PSMD14) MPN heterodimer solved using a nanobody-stabilized fusion protein. Full deubiquitylation activity requires incorporation into the 26S proteasome and is coupled to ATP hydrolysis. Activation is normally suppressed by low intrinsic ubiquitin affinity, an insertion segment blocking the substrate access channel, and a conformationally unstable catalytic loop in Rpn11. Docking into proteasome EM density shows Rpn11 contacts ATPase subunits that stabilize the active conformation.\",\n      \"method\": \"X-ray crystallography, nanobody co-crystallization, in vitro deubiquitylation assay, EM density docking\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional biochemical validation, replicates findings of PMID 24463465 with orthogonal methods\",\n      \"pmids\": [\"24516147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the human PSMD7/Mov34 MPN domain (residues 1–186) solved at 1.96 Å reveals a dimeric architecture via domain swapping. The MPN domain lacks the conserved zinc-coordinating residues present in catalytically active MPN proteins (Rpn11, Csn5), explaining why PSMD7 has no intrinsic isopeptidase activity; the MPN domain therefore serves a structural rather than catalytic role.\",\n      \"method\": \"X-ray crystallography (1.96 Å and 3.0 Å), size-exclusion chromatography, dynamic light scattering\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with solution biophysical validation confirming dimer; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17559875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The N-terminal eight residues (1–8) of human PSMD7/Mov34 MPN domain are required for proper folding and thermal stability of the domain; truncation mutants lacking residues 1–8 show reduced alpha-helical content and lower expression levels.\",\n      \"method\": \"Protease resistance assay, circular dichroism spectroscopy, thermal stability measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — biophysical characterization in single lab with multiple methods but no functional rescue experiment\",\n      \"pmids\": [\"16842755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"PSMD7 (p40) was identified and cloned as a regulatory subunit of the human 26S proteasome. The protein contains a C-terminal KEKE motif (alternating Lys/Glu residues) and is homologous to the mouse Mov-34 gene product, establishing it as a novel essential regulatory subunit of the 26S proteasome.\",\n      \"method\": \"cDNA cloning, sequence analysis, biochemical characterization of 26S proteasome subunit composition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical identification as proteasome subunit; foundational cloning and characterization paper\",\n      \"pmids\": [\"7755639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"HIV-1 Vpr directly interacts with hVIP/MOV34 (PSMD7) both in vitro (GST pulldown) and in vivo (co-immunoprecipitation). Vpr-induced cell cycle arrest at G2/M correlates with a change in PSMD7 subcellular localization from nuclear to perinuclear, accompanied by inhibition of maturation-promoting factor (MPF)-associated histone H1 kinase activity.\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, subcellular localization imaging, histone H1 kinase assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction assays plus functional localization shift linked to cell cycle phenotype, single lab\",\n      \"pmids\": [\"9520381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The carboxyl-terminal domain of hVIP/MOV34 (PSMD7) is required for its interaction with HIV-1 Vpr. In the absence of Vpr, full-length PSMD7 is cytoplasmic; expression of Vpr shifts PSMD7 to a nuclear localization. C-terminal deletion mutants do not respond to Vpr or to dexamethasone, indicating that this domain also mediates glucocorticoid receptor-dependent nucleocytoplasmic shuttling of PSMD7.\",\n      \"method\": \"Deletion mutant mapping, co-immunoprecipitation, subcellular localization imaging, glucocorticoid receptor signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with multiple deletion mutants plus localization and signaling functional readouts, single lab\",\n      \"pmids\": [\"12237292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In S. cerevisiae, the C-terminal 30 amino acids of Rpn8 (PSMD7 ortholog) are sufficient for binding to the C terminus of Pih1 (R2TP complex scaffold). This direct interaction mediates ubiquitin-independent proteasomal degradation of Pih1; truncation of the Rpn8 C-terminal disordered region does not affect proteasome assembly but specifically blocks Pih1 degradation both in vivo and in vitro.\",\n      \"method\": \"Co-immunoprecipitation, truncation mutant analysis, in vitro and in vivo degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding domain mapped, in vitro degradation assay performed, single lab with two complementary approaches\",\n      \"pmids\": [\"27053109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMD7 deubiquitinase activity stabilizes RAD23B protein in gastric cancer cells. PSMD7 co-immunoprecipitates with RAD23B, and PSMD7 knockdown enhances RAD23B ubiquitination and degradation, reducing XPC levels and impairing DNA damage repair.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown with protein stability measurement, xenograft mouse model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed by Co-IP, ubiquitination status measured, functional rescue experiment, single lab\",\n      \"pmids\": [\"34512150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSMD7 deubiquitinates and stabilizes SOX2 protein in pancreatic cancer cells, thereby activating Notch1 signaling. Restoration of SOX2 expression rescued the anti-tumor effects of PSMD7 knockdown, placing PSMD7 upstream of SOX2 in the Notch1 pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function experiments in vitro and in vivo, epistasis rescue experiment\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and ubiquitination assay with epistasis rescue, single lab\",\n      \"pmids\": [\"38494478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMD7 interacts with RAB1A and reduces its ubiquitination, stabilizing RAB1A protein post-translationally in bladder cancer cells. RAB1A functions as a downstream effector of PSMD7 in promoting bladder cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, overexpression rescue experiment\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with ubiquitination assay, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"38040402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSMD7 knockdown in breast cancer cells promotes ubiquitin-dependent degradation of p21 and p27, leading to G0/G1 cell cycle arrest, senescence, and apoptosis, indicating that PSMD7 normally stabilizes these cell cycle inhibitors.\",\n      \"method\": \"shRNA knockdown, cell cycle analysis, protein stability assay\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect evidence of substrate stabilization from KD phenotype, no direct ubiquitination or interaction assay reported\",\n      \"pmids\": [\"33042429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMD7 knockdown in non-small cell lung cancer cells increases p53 protein levels and induces p21 and PUMA expression in a p53-dependent manner, indicating PSMD7 normally promotes p53 degradation via the proteasome.\",\n      \"method\": \"shRNA knockdown, western blot, xenograft mouse model\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect pathway placement via KD phenotype, no direct ubiquitination or Co-IP assay reported for p53\",\n      \"pmids\": [\"34234864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD7 knockdown in esophageal squamous cell carcinoma reduces proteasomal function and suppresses mTOR/p70S6K pathway activity; conversely, PSMD7 overexpression increases phosphorylation of mTOR (Ser2448) and p70S6K (Thr421/Ser424), placing PSMD7 upstream of this pathway.\",\n      \"method\": \"shRNA knockdown, lentiviral overexpression, western blot for pathway phosphorylation, xenograft mouse model\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological pathway readout without direct substrate or interaction assay, single lab\",\n      \"pmids\": [\"29632807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Murine Mov34 (PSMD7 ortholog) binds the 3'-stem-loop structure of the Japanese encephalitis virus (JEV) 3'-noncoding region RNA, as detected by UV crosslinking, Northwestern blotting, and competition with viral genomic RNA.\",\n      \"method\": \"Gel retardation assay, UV crosslinking, Northwestern blotting, cDNA library screen, competition RNA binding assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct RNA-binding demonstrated biochemically but functional consequence for proteasome biology not established; single lab\",\n      \"pmids\": [\"10799585\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD7 (Rpn8/MOV34) is a non-catalytic MPN-domain subunit of the 26S proteasome 19S regulatory particle that forms an obligate heterodimer with the deubiquitinase Rpn11/PSMD14 via two conserved interfaces; this heterodimer is required for proteasome lid assembly and for positioning Rpn11 at the ATPase ring entrance where, upon ATP hydrolysis, ubiquitin chains are removed from translocating substrates in a linkage-nonspecific, co-translational manner, while PSMD7's own MPN domain lacks the conserved JAMM zinc-coordination motif and therefore contributes a structural rather than catalytic function; outside the proteasome, PSMD7 also stabilizes specific substrates (RAD23B, SOX2, RAB1A) by reducing their ubiquitination, interacts with HIV-1 Vpr through its C-terminal domain triggering nucleocytoplasmic redistribution, and mediates ubiquitin-independent degradation of certain proteins (e.g., Pih1) through a direct interaction with its C-terminal disordered region.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMD7 (Rpn8/Mov34) is a non-catalytic MPN-domain subunit of the 26S proteasome 19S regulatory particle that was originally cloned as the human p40 regulatory subunit homologous to mouse Mov-34 [#4]. Its defining mechanistic role is to form an obligate heterodimer with the deubiquitinase Rpn11/PSMD14 through two distinct MPN-MPN interfaces, an arrangement resolved by high-resolution crystal structures of the heterodimer [#0, #1]. Although both partners carry MPN domains, the PSMD7 domain lacks the conserved zinc-coordinating residues of catalytically active MPN proteins and therefore contributes structural support rather than isopeptidase activity, with its N-terminal residues required for proper folding and stability [#2, #3]. Full deubiquitylation by the heterodimer is achieved only upon incorporation into the 26S proteasome and is coupled to ATP hydrolysis, with Rpn11 positioned at the ATPase ring where it removes ubiquitin chains from translocating substrates in a linkage-nonspecific manner [#0, #1]. Beyond its core proteasomal function, PSMD7 acts on specific clients: its C-terminal disordered region directly binds and mediates ubiquitin-independent degradation of Pih1 [#7], and in cancer cells PSMD7 reduces ubiquitination to stabilize substrates including RAD23B and SOX2 [#8, #9]. PSMD7 is also a target of HIV-1 Vpr, which binds its C-terminal domain and triggers a shift in PSMD7 nucleocytoplasmic distribution linked to G2/M cell cycle arrest [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the molecular identity of PSMD7 by cloning it as a regulatory subunit of the human 26S proteasome, anchoring all later mechanistic work to a defined proteasome component.\",\n      \"evidence\": \"cDNA cloning and biochemical analysis of 26S proteasome subunit composition\",\n      \"pmids\": [\"7755639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve the subunit's structural role or catalytic status\", \"No interaction partners within the proteasome defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed PSMD7 is a direct target of HIV-1 Vpr, connecting a proteasome subunit to viral manipulation of the cell cycle.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, and histone H1 kinase assay linking Vpr binding to G2/M arrest\",\n      \"pmids\": [\"9520381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding region on PSMD7 not yet mapped\", \"Mechanistic link between localization shift and MPF inhibition not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Tested whether PSMD7 has RNA-binding capacity, identifying direct binding to the JEV 3' noncoding RNA stem-loop.\",\n      \"evidence\": \"UV crosslinking, Northwestern blotting, and competition RNA-binding assays with murine Mov34\",\n      \"pmids\": [\"10799585\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional consequence for proteasome biology not established\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped the Vpr-binding and shuttling determinant to the PSMD7 C-terminal domain, explaining how Vpr and glucocorticoid signaling redirect PSMD7 localization.\",\n      \"evidence\": \"Deletion mutant mapping with co-IP, localization imaging, and glucocorticoid receptor signaling assays\",\n      \"pmids\": [\"12237292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular consequence of nuclear redistribution incompletely defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Determined the human PSMD7 MPN domain structure and demonstrated it lacks the catalytic zinc-coordination motif, establishing it as a non-catalytic structural subunit.\",\n      \"evidence\": \"X-ray crystallography (1.96 Å) with size-exclusion chromatography and dynamic light scattering\",\n      \"pmids\": [\"17559875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain-swapped dimer biological relevance versus heterodimer not resolved\", \"No proteasome-context structure\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the Rpn11-Rpn8 (PSMD14-PSMD7) heterodimer at atomic resolution and explained why the deubiquitinase is promiscuous and ATP-coupled, defining the core mechanism of co-translational chain removal.\",\n      \"evidence\": \"Two independent crystal structures (2.0 Å; nanobody-stabilized) with mutagenesis, in vitro deubiquitylation assays, and EM density docking\",\n      \"pmids\": [\"24463465\", \"24516147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PSMD7's specific contribution to lid assembly not separately dissected\", \"Dynamics of activation upon proteasome incorporation not fully captured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a proteasome-assembly-independent role for the PSMD7 C-terminus in mediating ubiquitin-independent degradation of Pih1, revealing a substrate-recruitment function distinct from the catalytic heterodimer.\",\n      \"evidence\": \"Truncation mapping with in vitro and in vivo degradation assays in S. cerevisiae\",\n      \"pmids\": [\"27053109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of ubiquitin-independent recruitment to other substrates unknown\", \"Structural basis of disordered-region binding not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PSMD7 stabilizes RAD23B by reducing its ubiquitination, linking PSMD7 to DNA damage repair via XPC in cancer cells.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, shRNA knockdown with stability measurement, and xenograft model\",\n      \"pmids\": [\"34512150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization is direct deubiquitination by PSMD7 versus indirect not distinguished\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the substrate-stabilization role to SOX2, placing PSMD7 upstream of Notch1 signaling through deubiquitination-dependent SOX2 stabilization.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and epistasis rescue in pancreatic cancer cells in vitro and in vivo\",\n      \"pmids\": [\"38494478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalytic mechanism for an MPN domain lacking the JAMM motif not reconciled\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMD7, whose MPN domain lacks catalytic residues, mediates substrate-specific stabilization and ubiquitin-independent degradation outside the Rpn11 heterodimer remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for substrate-specific client binding outside the proteasome\", \"Unclear whether reported deubiquitination of clients is intrinsic or relies on associated DUBs\", \"Relationship between proteasomal and extra-proteasomal pools undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 8, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"complexes\": [\"26S proteasome 19S regulatory particle\"],\n    \"partners\": [\"PSMD14\", \"Vpr\", \"RAD23B\", \"SOX2\", \"RAB1A\", \"Pih1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}