{"gene":"PSMC1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2000,"finding":"The 26S proteasome ATPase subunit S4 (PSMC1) forms specific heterodimeric and higher-order complexes within the 19S regulatory complex. S4 pairs with S7 as an ATPase dimer, and both the non-ATPase subunit S2 (binding the NH2-terminal region of S4) and S5b (binding the COOH-terminal two-thirds of S4) assemble with the S4-S7 dimer to form a tetramer. Domain-mapping with chimeric ATPases identified distinct binding surfaces on S4 for S2 and S5b.","method":"In vitro co-translation/sedimentation, immunoprecipitation of reticulocyte lysate-translated subunits, chimeric ATPase domain-swap experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP and domain-mapping with chimeric proteins, moderate evidence from single lab with multiple orthogonal methods","pmids":["10625621"],"is_preprint":false},{"year":2012,"finding":"N-myristoylation of the Rpt2 subunit (yeast ortholog of PSMC1) at its N-terminus controls the intracellular localization of the 26S proteasome. Mutation of the N-myristoylation site causes diffusion of nuclear proteasomes into the cytoplasm where they form aggregates, without altering molecular assembly or peptidase activity. Loss of N-myristoylation leads to accumulation of polyubiquitinated proteins and a growth defect under protein-misfolding stress.","method":"Site-directed mutagenesis of N-myristoylation site, fluorescence microscopy of proteasome localization, peptidase activity assays, polyubiquitin accumulation assays, growth assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO/mutation with defined cellular phenotype and functional consequence for localization, multiple orthogonal readouts","pmids":["23102099"],"is_preprint":false},{"year":2015,"finding":"N-myristoylation of yeast Rpt2 (PSMC1 ortholog) specifically regulates the nuclear versus cytoplasmic distribution of the proteasome and thereby controls compartment-specific protein quality control. In N-myristoylation-deficient mutants, nuclear ubiquitination of proteins with nucleo-cytoplasmic localization is upregulated, and levels of nuclear-import-associated Hsp70 chaperones (Ssa, Sse1) are elevated while the nuclear-export chaperone Ssb is reduced, indicating disruption of nuclear protein quality control.","method":"Quantitative ubiquitinome profiling (anti-K-ε-GG antibody enrichment, MS), protein-level quantification in myristoylation-site mutant yeast strains","journal":"Journal of proteomics","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative proteomics with defined mutant, single lab","pmids":["26344132"],"is_preprint":false},{"year":2011,"finding":"The Arabidopsis RPT2 subunit (plant ortholog of PSMC1) is essential for 26S proteasome assembly. The C-terminal hydrophobic sequence of RPT2, which docks the RPT ATPase ring onto the core particle (CP), is required for function, as is ATP binding/hydrolysis activity. Loss of RPT2 destabilizes the 26S complex and causes accumulation of ubiquitinated proteins, impaired histone dynamics, and developmental defects. Functional redundancy exists between RPT2a and RPT2b paralogs.","method":"Genetic analysis of double null mutants, complementation with wild-type and ATP-binding/C-terminal mutants, 26S complex stability assays, polyubiquitin accumulation assays","journal":"The Plant cell","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO with defined phenotypic and biochemical readouts; plant ortholog reduces direct applicability to human PSMC1","pmids":["22158466"],"is_preprint":false},{"year":1996,"finding":"The 26S proteasome contains a 19S regulatory complex composed of multiple ATPases (including the S4/PSMC1 subunit) that form a ring and are necessary for binding and degrading ubiquitinated protein substrates. The ATPase subunits are essential for unfolding substrates and translocating them into the 20S core particle. The regulatory complex ATPases bind ubiquitinated substrates and couple ATP hydrolysis to substrate processing.","method":"Biochemical reconstitution, peptidase activity assays, review of structural and functional data across multiple studies","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — foundational review synthesizing reconstitution and structural data from multiple labs; highly replicated findings","pmids":["8811196"],"is_preprint":false}],"current_model":"PSMC1 (S4; yeast ortholog Rpt2) is an ATPase subunit of the 19S regulatory particle of the 26S proteasome that forms specific heterodimeric (with S7/PSMC2) and tetrameric (with S2, S5b, S7) subcomplexes via distinct N- and C-terminal binding surfaces, participates in ATP-dependent unfolding and translocation of ubiquitinated substrates into the 20S core particle, and is regulated by N-terminal myristoylation that controls nuclear localization of the proteasome and thereby compartment-specific protein quality control."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing that PSMC1 is one of several ATPase subunits in the 19S regulatory particle answered the question of how the 26S proteasome recognizes, unfolds, and translocates ubiquitinated substrates into the 20S core for proteolysis.","evidence":"Biochemical reconstitution, peptidase activity assays, and structural analysis across multiple laboratories","pmids":["8811196"],"confidence":"High","gaps":["Individual contributions of each ATPase subunit to substrate processing were not resolved","No structural model of the intact 19S base at atomic resolution at this time"]},{"year":2000,"claim":"Mapping the subunit interaction surfaces of PSMC1 revealed that it forms a specific heterodimer with S7 and that S2 and S5b bind distinct regions (N-terminal and C-terminal, respectively), defining the modular assembly pathway of the 19S base.","evidence":"In vitro co-translation/sedimentation, immunoprecipitation of reticulocyte lysate-translated subunits, chimeric ATPase domain-swap experiments","pmids":["10625621"],"confidence":"High","gaps":["Whether these subcomplexes represent on-pathway assembly intermediates in vivo was not determined","Structural basis for selectivity of S2 vs S5b binding to different PSMC1 surfaces was not resolved"]},{"year":2011,"claim":"Genetic analysis of Arabidopsis RPT2 (PSMC1 ortholog) demonstrated that both the C-terminal CP-docking motif and ATPase catalytic activity are essential for 26S proteasome stability and ubiquitin-dependent proteolysis in vivo.","evidence":"Genetic knockout/complementation with wild-type and mutant RPT2 in Arabidopsis, 26S complex stability assays, polyubiquitin accumulation assays","pmids":["22158466"],"confidence":"Medium","gaps":["Findings are from a plant ortholog; direct validation in mammalian PSMC1 was not performed","Contribution of the C-terminal motif relative to other RPT subunit tails was not individually resolved"]},{"year":2012,"claim":"Discovery that N-myristoylation of Rpt2/PSMC1 controls nuclear localization of the 26S proteasome revealed a post-translational mechanism for compartment-specific proteasome targeting, independent of assembly or catalytic activity.","evidence":"Site-directed mutagenesis of N-myristoylation site in yeast, fluorescence microscopy, peptidase activity assays, polyubiquitin accumulation assays, growth assays under stress","pmids":["23102099"],"confidence":"High","gaps":["Mechanism by which myristoylation anchors proteasomes in the nucleus is unknown","Whether mammalian PSMC1 N-myristoylation has the same localization function was not tested"]},{"year":2015,"claim":"Quantitative ubiquitinome profiling of myristoylation-deficient Rpt2 mutants demonstrated that loss of nuclear proteasome enrichment specifically upregulates ubiquitination of nucleo-cytoplasmic proteins and alters chaperone networks, establishing PSMC1 myristoylation as a regulator of compartment-specific protein quality control.","evidence":"Anti-K-ε-GG antibody enrichment and quantitative mass spectrometry in yeast myristoylation-site mutants","pmids":["26344132"],"confidence":"Medium","gaps":["Single-lab proteomics study; independent confirmation in additional systems is lacking","Which specific nuclear substrates are direct clients of myristoylation-dependent proteasome targeting is unresolved"]},{"year":null,"claim":"The mechanism by which N-myristoylation physically anchors the proteasome in the nucleus, and whether this modification regulates PSMC1 function in human cells, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biophysical model for how myristoylation mediates nuclear retention","Mammalian validation of myristoylation-dependent localization is absent","Individual catalytic contribution of PSMC1 ATPase activity versus other RPT subunits in human proteasomes is not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,4]}],"complexes":["26S proteasome","19S regulatory particle"],"partners":["PSMC2","PSMD1","PSMD11"],"other_free_text":[]},"mechanistic_narrative":"PSMC1 (also called S4; yeast ortholog Rpt2) is an AAA-ATPase subunit of the 19S regulatory particle of the 26S proteasome that couples ATP hydrolysis to the unfolding and translocation of ubiquitinated substrates into the 20S core particle for degradation [PMID:8811196]. Within the 19S base, PSMC1 forms a specific heterodimer with S7/PSMC2 and assembles into higher-order subcomplexes with S2 and S5b through distinct N-terminal and C-terminal binding surfaces, and its C-terminal hydrophobic motif is required for docking the ATPase ring onto the core particle [PMID:10625621, PMID:22158466]. N-myristoylation of the PSMC1 N-terminus governs nuclear localization of the 26S proteasome; loss of this modification causes proteasome redistribution to the cytoplasm, accumulation of polyubiquitinated nuclear proteins, altered chaperone levels, and impaired protein quality control under stress [PMID:23102099, PMID:26344132]."},"prefetch_data":{"uniprot":{"accession":"P62191","full_name":"26S proteasome regulatory subunit 4","aliases":["26S proteasome AAA-ATPase subunit RPT2","Proteasome 26S subunit ATPase 1"],"length_aa":440,"mass_kda":49.2,"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. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides","subcellular_location":"Cytoplasm; Nucleus; Membrane","url":"https://www.uniprot.org/uniprotkb/P62191/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMC1","classification":"Common Essential","n_dependent_lines":1167,"n_total_lines":1208,"dependency_fraction":0.9660596026490066},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMA6","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0},{"gene":"PSMB5","stoichiometry":10.0},{"gene":"PSMB7","stoichiometry":10.0},{"gene":"PSMC2","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/PSMC1","total_profiled":1310},"omim":[{"mim_id":"620071","title":"BIRK-AHARONI SYNDROME; BKAH","url":"https://www.omim.org/entry/620071"},{"mim_id":"619669","title":"PIERCER OF MICROTUBULE WALL 2; PIERCE2","url":"https://www.omim.org/entry/619669"},{"mim_id":"617858","title":"PROTEASOME INHIBITOR SUBUNIT 1; PSMF1","url":"https://www.omim.org/entry/617858"},{"mim_id":"603481","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 13; PSMD13","url":"https://www.omim.org/entry/603481"},{"mim_id":"602708","title":"PROTEASOME 26S SUBUNIT, ATPase, 6; PSMC6","url":"https://www.omim.org/entry/602708"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":294.5}],"url":"https://www.proteinatlas.org/search/PSMC1"},"hgnc":{"alias_symbol":["S4","p56","RPT2"],"prev_symbol":[]},"alphafold":{"accession":"P62191","domains":[{"cath_id":"2.40.50.140","chopping":"103-161","consensus_level":"high","plddt":85.0814,"start":103,"end":161},{"cath_id":"3.40.50.300","chopping":"170-351","consensus_level":"high","plddt":82.9433,"start":170,"end":351},{"cath_id":"1.10.8.60","chopping":"357-430","consensus_level":"high","plddt":84.5065,"start":357,"end":430}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62191","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62191-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62191-F1-predicted_aligned_error_v6.png","plddt_mean":77.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMC1","jax_strain_url":"https://www.jax.org/strain/search?query=PSMC1"},"sequence":{"accession":"P62191","fasta_url":"https://rest.uniprot.org/uniprotkb/P62191.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62191/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62191"}},"corpus_meta":[{"pmid":"7527085","id":"PMC_7527085","title":"Reversal 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/14743216","citation_count":841,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528300","id":"PMC_14528300","title":"The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528300","citation_count":798,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12859895","id":"PMC_12859895","title":"Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12859895","citation_count":763,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528301","id":"PMC_14528301","title":"HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528301","citation_count":679,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19060904","id":"PMC_19060904","title":"An empirical framework for binary interactome mapping.","date":"2008","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/19060904","citation_count":652,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14527406","id":"PMC_14527406","title":"HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/14527406","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47786,"output_tokens":1404,"usd":0.082209},"stage2":{"model":"claude-opus-4-6","input_tokens":4363,"output_tokens":1621,"usd":0.09351},"total_usd":0.386979,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":59135,"output_tokens":2560,"usd":0.107902},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5006,"output_tokens":1755,"usd":0.103358}},"stage1_raw":"Looking at the corpus, I need to identify papers about PSMC1 (the human 26S proteasome regulatory subunit ATPase 1, also known as S4 or Rpt2 in yeast/other organisms).\n\nThe key paper is PMID:10625621, which directly studies S4 (PSMC1) as part of the 26S proteasome regulatory complex. Papers about yeast Rpt2 (PMID:23102099, PMID:26344132) are orthologs. Papers about Arabidopsis RPT2 (PMID:22158466) are also orthologs of the proteasome ATPase. The vast majority of papers in this corpus are about completely unrelated proteins that happen to use \"S4\" in their names (ion channel S4 segments, reovirus S4 gene, ribosomal protein S4, etc.) — these are symbol collisions and should be excluded.\n\nLet me extract findings specifically about PSMC1/S4 (proteasome ATPase subunit):\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"PSMC1 (S4) forms a specific tetramer with proteasome regulatory complex subunits S2, S5b, and S7 (another ATPase). S2 binds the N-terminal region of S4, while S5b binds the C-terminal two-thirds of S4, as demonstrated by co-translation, sedimentation, and chimeric ATPase domain-swap experiments.\",\n      \"method\": \"In vitro co-translation, sedimentation analysis, immunoprecipitation, chimeric ATPase domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal domain mapping with chimeric proteins plus co-translation and immunoprecipitation in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"10625621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"N-myristoylation of the Rpt2 subunit (yeast ortholog of PSMC1) controls intracellular localization of the 26S proteasome; mutation of the N-myristoylation site causes nuclear proteasomes to diffuse into the cytoplasm and form aggregates, leading to accumulation of polyubiquitinated proteins and a growth defect under protein misfolding stress, without altering proteasome assembly or peptidase activity.\",\n      \"method\": \"Site-directed mutagenesis of N-myristoylation site, fluorescence microscopy, peptidase activity assay, polyubiquitin accumulation assay, growth assays in yeast\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/mutagenesis with defined cellular phenotype and multiple functional readouts in yeast ortholog\",\n      \"pmids\": [\"23102099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-myristoylation of yeast Rpt2 (PSMC1 ortholog) regulates nucleo-cytoplasmic distribution of the proteasome and controls compartment-specific protein quality control; loss of myristoylation elevates ubiquitination of nucleo-cytoplasmic proteins and alters levels of Hsp70 chaperones involved in nuclear import/export of misfolded proteins.\",\n      \"method\": \"Quantitative ubiquitinome mass spectrometry using anti-K-ε-GG antibody in wild-type vs. N-myristoylation mutant yeast strains\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab, quantitative MS-based ubiquitinome profiling in yeast ortholog\",\n      \"pmids\": [\"26344132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Arabidopsis RPT2 (plant ortholog of PSMC1) is essential for 26S proteasome assembly and stability; rpt2a rpt2b double null mutants are blocked in gamete transmission, and rpt2a single mutants show impaired leaf, root, trichome, and pollen development. The C-terminal hydrophobic sequence that docks the RPT ring onto the core protease (CP) is required for function, as is ATP binding/hydrolysis.\",\n      \"method\": \"Genetic analysis of Arabidopsis double null mutants, phenotypic characterization, complementation with domain mutants (ATP binding/hydrolysis and C-terminal docking sequence)\",\n      \"journal\": \"The Plant cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis and domain mutagenesis in plant ortholog; functional domains conserved with mammalian PSMC1\",\n      \"pmids\": [\"22158466\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC1 (S4) is an AAA-ATPase subunit of the 19S regulatory complex of the 26S proteasome that forms a specific tetramer with subunits S2, S5b, and the ATPase S7 through defined N- and C-terminal domain interactions; its N-myristoylation (in the yeast ortholog Rpt2) controls nuclear localization of the proteasome and is required for compartment-specific protein quality control, while its C-terminal hydrophobic docking sequence is essential for assembly onto the core protease and for proper proteasome function.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification Analysis:**\n\nThe query gene is PSMC1 — the 19S proteasome regulatory particle ATPase subunit (also known as S4 or Rpt2 in yeast, or the 26S proteasome subunit S4 in mammals). This is the ATPase component of the 26S proteasome lid/base.\n\nKey papers about PSMC1/S4 (proteasome subunit):\n- Paper [29] from Retrieved: \"Mapping subunit contacts in the regulatory complex of the 26S proteasome. S2 and S5b form a tetramer with ATPase subunits S4 and S7\" — this S4 refers to the 26S proteasome ATPase subunit. KEEP\n- Paper [39] from Retrieved: \"N-myristoylation of the Rpt2 subunit regulates intracellular localization of the yeast 26S proteasome\" — Rpt2 is the yeast ortholog of PSMC1. KEEP\n- Paper [83] from Retrieved: \"N-Myristoylation of the Rpt2 subunit of the yeast 26S proteasome is implicated in the subcellular compartment-specific protein quality control system\" — yeast Rpt2/PSMC1 ortholog. KEEP\n- Paper [49] from Retrieved: \"The RPT2 subunit of the 26S proteasome directs complex assembly, histone dynamics, and gametophyte and sporophyte development in Arabidopsis\" — RPT2 in plants is a proteasome subunit. However, the cellular context (plant development, histone dynamics) is consistent with the mammalian proteasome function. But this is Arabidopsis RPT2 as a proteasome subunit — consistent ortholog. KEEP\n- Paper [88] from Retrieved: \"Transforming growth factor-beta is an autocrine mitogen for a novel androgen-responsive murine prostatic smooth muscle cell line, PSMC1\" — PSMC1 here is a cell line name, NOT the gene PSMC1. EXCLUDE (alias collision — cell line name).\n\nMost other retrieved papers are about completely different \"S4\" entities (potassium channel S4 segment, ribosomal protein S4, reovirus S4 gene, p56lck, RPT2 in plants as phototropin signaling, etc.) — EXCLUDE.\n\nFrom the gene2pubmed curated papers:\n- [1] Structure and functions of the 20S and 26S proteasomes — KEEP (describes the 26S proteasome including its ATPase subunits)\n- [2-30] The rest are mostly interactome mapping studies, APOBEC3G/HIV papers, etc. — these are large-scale interactome studies that detected PSMC1 interactions but don't provide mechanistic discoveries specific to PSMC1. The APOBEC3G papers are clearly unrelated. Large interactome papers (BioPlex, HuRI, etc.) don't provide PSMC1-specific mechanistic findings.\n\nLet me now extract discoveries from KEPT papers:\n\n**KEPT papers:**\n- PMID 10625621 (paper [29]): S4 (PSMC1) forms tetramer with S2, S5b, S7 — maps subunit contacts\n- PMID 23102099 (paper [39]): N-myristoylation of Rpt2 controls intracellular localization of 26S proteasome\n- PMID 26344132 (paper [83]): N-myristoylation of Rpt2 regulates nucleo-cytoplasmic localization\n- PMID 22158466 (paper [49]): Arabidopsis RPT2 (plant ortholog) — assembly role; C-terminal hydrophobic sequence docks RPT ring onto CP; ATP binding/hydrolysis required. KEEP as ortholog.\n- PMID 8811196 (gene2pubmed [1]): General proteasome review — describes ATPase ring, mentions subunits\n- PMID 19489727 (gene2pubmed [6]): Review of proteasome — six ATPases form ring, drive unfolding and translocation\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"The 26S proteasome ATPase subunit S4 (PSMC1) forms specific heterodimeric and higher-order complexes within the 19S regulatory complex. S4 pairs with S7 as an ATPase dimer, and both the non-ATPase subunit S2 (binding the NH2-terminal region of S4) and S5b (binding the COOH-terminal two-thirds of S4) assemble with the S4-S7 dimer to form a tetramer. Domain-mapping with chimeric ATPases identified distinct binding surfaces on S4 for S2 and S5b.\",\n      \"method\": \"In vitro co-translation/sedimentation, immunoprecipitation of reticulocyte lysate-translated subunits, chimeric ATPase domain-swap experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and domain-mapping with chimeric proteins, moderate evidence from single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10625621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"N-myristoylation of the Rpt2 subunit (yeast ortholog of PSMC1) at its N-terminus controls the intracellular localization of the 26S proteasome. Mutation of the N-myristoylation site causes diffusion of nuclear proteasomes into the cytoplasm where they form aggregates, without altering molecular assembly or peptidase activity. Loss of N-myristoylation leads to accumulation of polyubiquitinated proteins and a growth defect under protein-misfolding stress.\",\n      \"method\": \"Site-directed mutagenesis of N-myristoylation site, fluorescence microscopy of proteasome localization, peptidase activity assays, polyubiquitin accumulation assays, growth assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/mutation with defined cellular phenotype and functional consequence for localization, multiple orthogonal readouts\",\n      \"pmids\": [\"23102099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-myristoylation of yeast Rpt2 (PSMC1 ortholog) specifically regulates the nuclear versus cytoplasmic distribution of the proteasome and thereby controls compartment-specific protein quality control. In N-myristoylation-deficient mutants, nuclear ubiquitination of proteins with nucleo-cytoplasmic localization is upregulated, and levels of nuclear-import-associated Hsp70 chaperones (Ssa, Sse1) are elevated while the nuclear-export chaperone Ssb is reduced, indicating disruption of nuclear protein quality control.\",\n      \"method\": \"Quantitative ubiquitinome profiling (anti-K-ε-GG antibody enrichment, MS), protein-level quantification in myristoylation-site mutant yeast strains\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative proteomics with defined mutant, single lab\",\n      \"pmids\": [\"26344132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Arabidopsis RPT2 subunit (plant ortholog of PSMC1) is essential for 26S proteasome assembly. The C-terminal hydrophobic sequence of RPT2, which docks the RPT ATPase ring onto the core particle (CP), is required for function, as is ATP binding/hydrolysis activity. Loss of RPT2 destabilizes the 26S complex and causes accumulation of ubiquitinated proteins, impaired histone dynamics, and developmental defects. Functional redundancy exists between RPT2a and RPT2b paralogs.\",\n      \"method\": \"Genetic analysis of double null mutants, complementation with wild-type and ATP-binding/C-terminal mutants, 26S complex stability assays, polyubiquitin accumulation assays\",\n      \"journal\": \"The Plant cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined phenotypic and biochemical readouts; plant ortholog reduces direct applicability to human PSMC1\",\n      \"pmids\": [\"22158466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The 26S proteasome contains a 19S regulatory complex composed of multiple ATPases (including the S4/PSMC1 subunit) that form a ring and are necessary for binding and degrading ubiquitinated protein substrates. The ATPase subunits are essential for unfolding substrates and translocating them into the 20S core particle. The regulatory complex ATPases bind ubiquitinated substrates and couple ATP hydrolysis to substrate processing.\",\n      \"method\": \"Biochemical reconstitution, peptidase activity assays, review of structural and functional data across multiple studies\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — foundational review synthesizing reconstitution and structural data from multiple labs; highly replicated findings\",\n      \"pmids\": [\"8811196\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC1 (S4; yeast ortholog Rpt2) is an ATPase subunit of the 19S regulatory particle of the 26S proteasome that forms specific heterodimeric (with S7/PSMC2) and tetrameric (with S2, S5b, S7) subcomplexes via distinct N- and C-terminal binding surfaces, participates in ATP-dependent unfolding and translocation of ubiquitinated substrates into the 20S core particle, and is regulated by N-terminal myristoylation that controls nuclear localization of the proteasome and thereby compartment-specific protein quality control.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMC1 (also called S4/Rpt2) is an AAA-ATPase subunit of the 19S regulatory particle of the 26S proteasome that assembles into a defined tetramer with subunits S2, S5b, and S7 through its N-terminal and C-terminal domains [PMID:10625621]. Its C-terminal hydrophobic docking sequence is essential for anchoring the ATPase ring onto the 20S core protease and for proteasome function, as is its ATPase activity [PMID:22158466]. N-myristoylation of its yeast ortholog Rpt2 controls nuclear localization of the 26S proteasome; loss of this modification causes nuclear proteasomes to redistribute into the cytoplasm and form aggregates, leading to accumulation of polyubiquitinated proteins and impaired compartment-specific protein quality control without affecting intrinsic proteasome assembly or peptidase activity [PMID:23102099, PMID:26344132].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing how PSMC1 is positioned within the 19S regulatory particle resolved a key assembly question: S4 nucleates a specific tetramer with S2 (binding the N-terminal region), S5b (binding the C-terminal two-thirds), and ATPase S7, defining a modular subassembly unit of the proteasome lid/base.\",\n      \"evidence\": \"In vitro co-translation, sedimentation analysis, immunoprecipitation, and chimeric ATPase domain-swap mapping in mammalian system\",\n      \"pmids\": [\"10625621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this tetramer represents a true on-pathway assembly intermediate in vivo is not demonstrated\",\n        \"No structural resolution of the S4–S2/S5b/S7 interfaces at atomic level\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Domain mutagenesis in the plant ortholog RPT2 demonstrated that PSMC1's C-terminal hydrophobic docking motif and ATPase catalytic activity are each individually essential for proteasome function, and that RPT2 is indispensable for 26S proteasome stability and organismal development.\",\n      \"evidence\": \"Genetic analysis of Arabidopsis rpt2a/rpt2b null mutants with complementation by C-terminal docking and ATP-binding/hydrolysis domain mutants\",\n      \"pmids\": [\"22158466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Phenotypic data are from the plant ortholog; direct mutagenesis of the mammalian C-terminal docking motif in a mammalian system has not been reported\",\n        \"Relative contributions of ATP binding vs. hydrolysis to docking were not separated\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that N-myristoylation of Rpt2 (yeast PSMC1) governs nuclear retention of the 26S proteasome revealed a lipid-modification-based mechanism for proteasome compartmentalization, separating localization control from assembly and catalytic activity.\",\n      \"evidence\": \"Site-directed mutagenesis of the N-myristoylation site in yeast Rpt2, fluorescence microscopy, peptidase activity and polyubiquitin accumulation assays, growth assays under stress\",\n      \"pmids\": [\"23102099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mammalian PSMC1 is N-myristoylated and whether the same localization mechanism operates in human cells is unknown\",\n        \"The molecular anchor or receptor that tethers myristoylated proteasomes in the nucleus is unidentified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantitative ubiquitinome profiling extended the myristoylation finding by showing that loss of Rpt2 myristoylation selectively increases ubiquitination of nucleo-cytoplasmic substrates and alters Hsp70 chaperone levels, establishing a link between proteasome localization and compartment-specific protein quality control.\",\n      \"evidence\": \"Anti-K-ε-GG ubiquitinome mass spectrometry comparing wild-type and N-myristoylation-mutant yeast strains\",\n      \"pmids\": [\"26344132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab proteomics study; independent validation of individual substrate changes has not been performed\",\n        \"Causal relationship between altered Hsp70 levels and mislocalized proteasomes is correlative\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether mammalian PSMC1 is N-myristoylated and whether this modification controls proteasome nuclear localization in human cells remains uncharacterized; the identity of the nuclear anchor for myristoylated proteasomes and structural details of the S4-nucleated tetramer within the intact 26S complex are also unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct evidence for PSMC1 myristoylation in mammalian cells\",\n        \"No high-resolution structure of the S4–S2–S5b–S7 assembly intermediate\",\n        \"Mechanism by which myristoylation anchors the proteasome in the nucleus is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"26S proteasome 19S regulatory particle\",\n      \"S4-S2-S5b-S7 tetramer\"\n    ],\n    \"partners\": [\n      \"PSMC2\",\n      \"PSMD1\",\n      \"PSMD5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMC1 (also called S4; yeast ortholog Rpt2) is an AAA-ATPase subunit of the 19S regulatory particle of the 26S proteasome that couples ATP hydrolysis to the unfolding and translocation of ubiquitinated substrates into the 20S core particle for degradation [PMID:8811196]. Within the 19S base, PSMC1 forms a specific heterodimer with S7/PSMC2 and assembles into higher-order subcomplexes with S2 and S5b through distinct N-terminal and C-terminal binding surfaces, and its C-terminal hydrophobic motif is required for docking the ATPase ring onto the core particle [PMID:10625621, PMID:22158466]. N-myristoylation of the PSMC1 N-terminus governs nuclear localization of the 26S proteasome; loss of this modification causes proteasome redistribution to the cytoplasm, accumulation of polyubiquitinated nuclear proteins, altered chaperone levels, and impaired protein quality control under stress [PMID:23102099, PMID:26344132].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that PSMC1 is one of several ATPase subunits in the 19S regulatory particle answered the question of how the 26S proteasome recognizes, unfolds, and translocates ubiquitinated substrates into the 20S core for proteolysis.\",\n      \"evidence\": \"Biochemical reconstitution, peptidase activity assays, and structural analysis across multiple laboratories\",\n      \"pmids\": [\"8811196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contributions of each ATPase subunit to substrate processing were not resolved\",\n        \"No structural model of the intact 19S base at atomic resolution at this time\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping the subunit interaction surfaces of PSMC1 revealed that it forms a specific heterodimer with S7 and that S2 and S5b bind distinct regions (N-terminal and C-terminal, respectively), defining the modular assembly pathway of the 19S base.\",\n      \"evidence\": \"In vitro co-translation/sedimentation, immunoprecipitation of reticulocyte lysate-translated subunits, chimeric ATPase domain-swap experiments\",\n      \"pmids\": [\"10625621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether these subcomplexes represent on-pathway assembly intermediates in vivo was not determined\",\n        \"Structural basis for selectivity of S2 vs S5b binding to different PSMC1 surfaces was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic analysis of Arabidopsis RPT2 (PSMC1 ortholog) demonstrated that both the C-terminal CP-docking motif and ATPase catalytic activity are essential for 26S proteasome stability and ubiquitin-dependent proteolysis in vivo.\",\n      \"evidence\": \"Genetic knockout/complementation with wild-type and mutant RPT2 in Arabidopsis, 26S complex stability assays, polyubiquitin accumulation assays\",\n      \"pmids\": [\"22158466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings are from a plant ortholog; direct validation in mammalian PSMC1 was not performed\",\n        \"Contribution of the C-terminal motif relative to other RPT subunit tails was not individually resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that N-myristoylation of Rpt2/PSMC1 controls nuclear localization of the 26S proteasome revealed a post-translational mechanism for compartment-specific proteasome targeting, independent of assembly or catalytic activity.\",\n      \"evidence\": \"Site-directed mutagenesis of N-myristoylation site in yeast, fluorescence microscopy, peptidase activity assays, polyubiquitin accumulation assays, growth assays under stress\",\n      \"pmids\": [\"23102099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which myristoylation anchors proteasomes in the nucleus is unknown\",\n        \"Whether mammalian PSMC1 N-myristoylation has the same localization function was not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantitative ubiquitinome profiling of myristoylation-deficient Rpt2 mutants demonstrated that loss of nuclear proteasome enrichment specifically upregulates ubiquitination of nucleo-cytoplasmic proteins and alters chaperone networks, establishing PSMC1 myristoylation as a regulator of compartment-specific protein quality control.\",\n      \"evidence\": \"Anti-K-ε-GG antibody enrichment and quantitative mass spectrometry in yeast myristoylation-site mutants\",\n      \"pmids\": [\"26344132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab proteomics study; independent confirmation in additional systems is lacking\",\n        \"Which specific nuclear substrates are direct clients of myristoylation-dependent proteasome targeting is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which N-myristoylation physically anchors the proteasome in the nucleus, and whether this modification regulates PSMC1 function in human cells, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biophysical model for how myristoylation mediates nuclear retention\",\n        \"Mammalian validation of myristoylation-dependent localization is absent\",\n        \"Individual catalytic contribution of PSMC1 ATPase activity versus other RPT subunits in human proteasomes is not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle\"\n    ],\n    \"partners\": [\n      \"PSMC2\",\n      \"PSMD1\",\n      \"PSMD11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}