{"gene":"COPRS","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2008,"finding":"COPR5 (cooperator of PRMT5) directly and specifically binds to PRMT5 both in vitro and in living cells, but not to other PRMT family members. Recombinant COPR5 binds to the amino terminus of histone H4 and is required to recruit PRMT5 to reconstituted nucleosomes in vitro. PRMT5 bound to COPR5 preferentially methylates histone H4 (R3) over histone H3 (R8), indicating that COPR5 modulates the substrate specificity of nuclear PRMT5-containing complexes. COPR5 depletion in cells strongly reduces PRMT5 recruitment on chromatin at the PRMT5 target gene CCNE1 (cyclin E1), and both COPR5 depletion and overexpression affect CCNE1 promoter expression.","method":"In vitro binding assays, co-immunoprecipitation in living cells, reconstituted nucleosome methylation assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, and reporter gene assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution, reciprocal Co-IP, nucleosome methylation assay, ChIP, and loss-of-function in cells; multiple orthogonal methods in a single rigorous study","pmids":["18404153"],"is_preprint":false},{"year":2021,"finding":"COPR5 interacts with the TIM barrel domain of PRMT5 via a consensus amino acid sequence GQF[D/E]DA[E/D], shared with other PRMT5 adaptor proteins pICln and RioK1. Peptide truncation and mutation studies defined the binding interface between COPR5 and PRMT5.","method":"Peptide truncation and mutation studies, protein crystallography (RioK1-derived peptide as structural comparator), and biochemical binding assays","journal":"Chembiochem : a European journal of chemical biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — peptide truncation/mutation with biochemical binding assays, single lab, two orthogonal methods","pmids":["33624332"],"is_preprint":false},{"year":2011,"finding":"COPR5 is required for myogenic differentiation: silencing COPR5 in C2C12 cells prevents irreversible cell cycle exit and differentiation into muscle cells, with strongly reduced induction of p21 and MYOGENIN (MYOG) and impaired PRMT5 recruitment to their promoters. COPR5 interacts with the RUNX1–CBFβ complex, contributing to targeting the COPR5–PRMT5 complex to these promoters. In vivo, COPR5 depletion delayed regeneration of cardiotoxin-injured mouse skeletal muscles.","method":"siRNA knockdown in C2C12 cells, ChIP, co-immunoprecipitation (COPR5 with RUNX1–CBFβ), in vivo cardiotoxin injury model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, loss-of-function with defined cellular and in vivo phenotype, single lab, multiple orthogonal methods","pmids":["22193545"],"is_preprint":false},{"year":2015,"finding":"COPR5 acts as a negative regulator of the Wnt target gene Dlk-1 during adipogenesis. Ablation of Copr5 in mice and MEFs impairs recruitment of both Prmt5 and β-catenin to the Dlk-1 promoter, leading to upregulation of Dlk-1 and delayed adipogenic conversion. Copr5 KO mice display reduced retroperitoneal white adipose tissue with fewer, larger adipocytes.","method":"Copr5 knockout mice, primary MEF culture, embryoid body differentiation, chromatin immunoprecipitation (ChIP), differential transcriptomic analysis","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, ChIP, in vivo and in vitro phenotyping, single lab","pmids":["25681392"],"is_preprint":false},{"year":2018,"finding":"Genetic inactivation of Coprs in mice disrupts spermatogonia-to-spermatid maturation. Mass spectrometry after co-immunoprecipitation with anti-Coprs antibody identified Miwi (a Piwi protein) as a Coprs-associated protein in testis. Coprs KO leads to deregulation of Miwi and pachytene pre-piRNA levels and derepression of LINE1 retrotransposons in spermatocytes, implicating COPR5 in Prmt5-mediated genome surveillance via the piRNA pathway.","method":"Coprs knockout mice, co-immunoprecipitation with mass spectrometry, LINE1 expression analysis, piRNA profiling","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype, Co-IP/MS for Miwi interaction, single lab","pmids":["30652083"],"is_preprint":false}],"current_model":"COPR5/COPRS is a nuclear histone H4-binding adaptor protein that specifically recruits PRMT5 to chromatin via direct interaction with PRMT5's TIM barrel domain (through a GQF[D/E]DA[E/D] motif), modulates PRMT5 substrate specificity toward histone H4-R3 methylation, and coordinates transcriptional programs required for cell cycle control, myogenic differentiation, adipogenesis, and piRNA-mediated retrotransposon silencing in spermatocytes."},"narrative":{"mechanistic_narrative":"COPRS (COPR5) is a nuclear adaptor protein that recruits the arginine methyltransferase PRMT5 to chromatin and shapes its histone substrate specificity, thereby coordinating transcriptional programs underlying cell-cycle control, differentiation, and germline genome surveillance [PMID:18404153]. It binds directly and specifically to PRMT5 — not other PRMT family members — and also engages the amino terminus of histone H4, and these dual interactions are required to deliver PRMT5 onto nucleosomes, where the COPR5-bound enzyme preferentially methylates histone H4-R3 over histone H3 [PMID:18404153]. The PRMT5 interaction is mediated by a GQF[D/E]DA[E/D] motif in COPRS that docks onto the PRMT5 TIM-barrel domain, a binding mode shared with the PRMT5 adaptors pICln and RioK1 [PMID:33624332]. Through this recruitment activity COPRS controls specific target genes: it is needed for PRMT5 loading at the CCNE1 promoter [PMID:18404153], and during myogenic differentiation it cooperates with the RUNX1–CBFβ complex to target PRMT5 to the p21 and MYOGENIN promoters, driving cell-cycle exit and muscle differentiation [PMID:22193545]. During adipogenesis it acts as a negative regulator of the Wnt target gene Dlk-1, supporting recruitment of both PRMT5 and β-catenin to the Dlk-1 promoter [PMID:25681392]. In the male germline COPRS associates with the Piwi protein Miwi and is required for normal piRNA levels and LINE1 retrotransposon repression in spermatocytes, linking it to PRMT5-mediated genome surveillance via the piRNA pathway [PMID:30652083].","teleology":[{"year":2008,"claim":"Established that PRMT5 requires a dedicated adaptor to reach chromatin and to bias its product specificity, answering how a soluble methyltransferase selectively methylates nucleosomal histone H4-R3 at specific genes.","evidence":"In vitro binding, reciprocal Co-IP in cells, reconstituted nucleosome methylation, ChIP, and siRNA knockdown at the CCNE1 locus","pmids":["18404153"],"confidence":"High","gaps":["Structural basis of the COPR5–PRMT5 interaction not yet resolved in this study","Mechanism by which H4 binding redirects specificity toward H4-R3 not defined at atomic resolution","Full repertoire of COPR5-dependent PRMT5 target genes not mapped"]},{"year":2011,"claim":"Showed how the COPR5–PRMT5 complex is targeted to specific promoters and linked it to a developmental program, answering what guides this adaptor to defined loci during differentiation.","evidence":"siRNA knockdown in C2C12 myoblasts, ChIP at p21/MYOG promoters, Co-IP with RUNX1–CBFβ, and an in vivo cardiotoxin muscle-injury model","pmids":["22193545"],"confidence":"Medium","gaps":["Whether RUNX1–CBFβ is the sole or general targeting partner is unclear","Direct versus indirect nature of the COPR5–RUNX1 interaction not fully resolved","Single-lab phenotype without independent replication"]},{"year":2015,"claim":"Extended the recruitment paradigm to Wnt-responsive transcription in adipogenesis, answering whether COPR5 also coordinates a non-myogenic differentiation program and a co-recruited transcription factor.","evidence":"Copr5 knockout mice and MEFs, embryoid body differentiation, ChIP showing loss of Prmt5 and β-catenin at the Dlk-1 promoter, transcriptomics","pmids":["25681392"],"confidence":"Medium","gaps":["Whether COPR5 directly interacts with β-catenin or recruits it indirectly is unresolved","Mechanism by which COPR5 acts as a negative regulator of Dlk-1 not detailed","Single-lab study"]},{"year":2018,"claim":"Connected COPR5 to germline genome surveillance, answering whether its adaptor function extends beyond transcriptional control into the piRNA pathway.","evidence":"Coprs knockout mice, Co-IP/mass spectrometry identifying Miwi, piRNA profiling, and LINE1 expression analysis in testis","pmids":["30652083"],"confidence":"Medium","gaps":["Whether the Coprs–Miwi association is direct or PRMT5-dependent is not established","Single Co-IP/MS identification without reciprocal validation","Mechanistic link between COPR5 and piRNA biogenesis versus retrotransposon silencing not separated"]},{"year":2021,"claim":"Defined the molecular interface of the COPR5–PRMT5 interaction, answering how the adaptor physically docks onto the enzyme and placing it within a shared family of PRMT5 adaptors.","evidence":"Peptide truncation/mutation and biochemical binding assays with crystallography of a RioK1-derived comparator peptide on the PRMT5 TIM-barrel domain","pmids":["33624332"],"confidence":"Medium","gaps":["No co-crystal structure of the COPR5 peptide itself with PRMT5","Functional consequence of disrupting the GQF[D/E]DA[E/D] motif in cells not tested here","How competing adaptors (pICln, RioK1) are selected at given loci is unknown"]},{"year":null,"claim":"How COPR5 adaptor choice, locus selection, and H4-R3 specificity are coordinated to switch between distinct transcriptional and germline genome-surveillance programs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking adaptor competition to context-specific PRMT5 output","Genome-wide map of COPR5-dependent PRMT5 targets across tissues lacking","Direct structural data for the COPR5–PRMT5 and COPR5–H4 contacts absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]}],"complexes":["COPR5–PRMT5 complex"],"partners":["PRMT5","RUNX1","CBFB","MIWI"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NQ92","full_name":"Coordinator of PRMT5 and differentiation stimulator","aliases":["Cooperator of PRMT5","Protein TTP1"],"length_aa":184,"mass_kda":20.1,"function":"Histone-binding protein required for histone H4 methyltransferase activity of PRMT5. Specifically required for histone H4 'Arg-3' methylation mediated by PRMT5, but not histone H3 'Arg-8' methylation, suggesting that it modulates the substrate specificity of PRMT5. Specifically interacts with the N-terminus of histone H4 but not with histone H3, suggesting that it acts by promoting the association between histone H4 and PRMT5. Involved in CCNE1 promoter repression. Plays a role in muscle cell differentiation by modulating the recruitment of PRMT5 to the promoter of genes involved in the coordination between cell cycle exit and muscle differentiation (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NQ92/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COPRS","classification":"Not Classified","n_dependent_lines":26,"n_total_lines":1208,"dependency_fraction":0.02152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COPRS","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COPRS"},"hgnc":{"alias_symbol":["TTP1","HSA272196","COPR5"],"prev_symbol":["C17orf79"]},"alphafold":{"accession":"Q9NQ92","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ92","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ92-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ92-F1-predicted_aligned_error_v6.png","plddt_mean":62.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COPRS","jax_strain_url":"https://www.jax.org/strain/search?query=COPRS"},"sequence":{"accession":"Q9NQ92","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQ92.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQ92/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ92"}},"corpus_meta":[{"pmid":"18404153","id":"PMC_18404153","title":"The histone-binding protein COPR5 is required for nuclear functions of the protein arginine methyltransferase PRMT5.","date":"2008","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/18404153","citation_count":109,"is_preprint":false},{"pmid":"22715108","id":"PMC_22715108","title":"The CopRS two-component system is responsible for resistance to copper in the cyanobacterium Synechocystis sp. PCC 6803.","date":"2012","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22715108","citation_count":70,"is_preprint":false},{"pmid":"21799779","id":"PMC_21799779","title":"The two-component signal transduction system CopRS of Corynebacterium glutamicum is required for adaptation to copper-excess stress.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21799779","citation_count":35,"is_preprint":false},{"pmid":"33361129","id":"PMC_33361129","title":"The Two-Component System CopRS Maintains Subfemtomolar Levels of Free Copper in the Periplasm of Pseudomonas aeruginosa Using a Phosphatase-Based Mechanism.","date":"2020","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/33361129","citation_count":33,"is_preprint":false},{"pmid":"33624332","id":"PMC_33624332","title":"Biochemical Investigation of the Interaction of pICln, RioK1 and COPR5 with the PRMT5-MEP50 Complex.","date":"2021","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/33624332","citation_count":22,"is_preprint":false},{"pmid":"22193545","id":"PMC_22193545","title":"The histone- and PRMT5-associated protein COPR5 is required for myogenic differentiation.","date":"2011","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/22193545","citation_count":21,"is_preprint":false},{"pmid":"25681392","id":"PMC_25681392","title":"The Wnt-target gene Dlk-1 is regulated by the Prmt5-associated factor Copr5 during adipogenic conversion.","date":"2015","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/25681392","citation_count":9,"is_preprint":false},{"pmid":"9413431","id":"PMC_9413431","title":"Yeast Crv4/Ttp1, a predicted type II membrane protein, is involved in an event important for growth, functionally overlapping with the event regulated by calcineurin- and Mpk1-mediated pathways.","date":"1997","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/9413431","citation_count":8,"is_preprint":false},{"pmid":"38070484","id":"PMC_38070484","title":"A novel tetratricopeptide-repeat protein, TTP1, forms complexes with glutamyl-tRNA reductase and protochlorophyllide oxidoreductase during tetrapyrrole biosynthesis.","date":"2024","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/38070484","citation_count":6,"is_preprint":false},{"pmid":"7992511","id":"PMC_7992511","title":"The nucleotide sequence of TTP1, a gene encoding a predicted type II membrane protein.","date":"1994","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7992511","citation_count":5,"is_preprint":false},{"pmid":"36622231","id":"PMC_36622231","title":"The Extracellular Electron Transport Pathway Reduces Copper for Sensing by the CopRS Two-Component System under Anaerobic Conditions in Listeria monocytogenes.","date":"2023","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/36622231","citation_count":3,"is_preprint":false},{"pmid":"30652083","id":"PMC_30652083","title":"Coprs inactivation leads to a derepression of LINE1 transposons in spermatocytes.","date":"2018","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/30652083","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7852,"output_tokens":1623,"usd":0.02395,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8382,"output_tokens":2644,"usd":0.054005,"stage2_stop_reason":"end_turn"},"total_usd":0.077955,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"COPR5 (cooperator of PRMT5) directly and specifically binds to PRMT5 both in vitro and in living cells, but not to other PRMT family members. Recombinant COPR5 binds to the amino terminus of histone H4 and is required to recruit PRMT5 to reconstituted nucleosomes in vitro. PRMT5 bound to COPR5 preferentially methylates histone H4 (R3) over histone H3 (R8), indicating that COPR5 modulates the substrate specificity of nuclear PRMT5-containing complexes. COPR5 depletion in cells strongly reduces PRMT5 recruitment on chromatin at the PRMT5 target gene CCNE1 (cyclin E1), and both COPR5 depletion and overexpression affect CCNE1 promoter expression.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation in living cells, reconstituted nucleosome methylation assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, and reporter gene assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution, reciprocal Co-IP, nucleosome methylation assay, ChIP, and loss-of-function in cells; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"18404153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COPR5 interacts with the TIM barrel domain of PRMT5 via a consensus amino acid sequence GQF[D/E]DA[E/D], shared with other PRMT5 adaptor proteins pICln and RioK1. Peptide truncation and mutation studies defined the binding interface between COPR5 and PRMT5.\",\n      \"method\": \"Peptide truncation and mutation studies, protein crystallography (RioK1-derived peptide as structural comparator), and biochemical binding assays\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — peptide truncation/mutation with biochemical binding assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"33624332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COPR5 is required for myogenic differentiation: silencing COPR5 in C2C12 cells prevents irreversible cell cycle exit and differentiation into muscle cells, with strongly reduced induction of p21 and MYOGENIN (MYOG) and impaired PRMT5 recruitment to their promoters. COPR5 interacts with the RUNX1–CBFβ complex, contributing to targeting the COPR5–PRMT5 complex to these promoters. In vivo, COPR5 depletion delayed regeneration of cardiotoxin-injured mouse skeletal muscles.\",\n      \"method\": \"siRNA knockdown in C2C12 cells, ChIP, co-immunoprecipitation (COPR5 with RUNX1–CBFβ), in vivo cardiotoxin injury model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, loss-of-function with defined cellular and in vivo phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22193545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"COPR5 acts as a negative regulator of the Wnt target gene Dlk-1 during adipogenesis. Ablation of Copr5 in mice and MEFs impairs recruitment of both Prmt5 and β-catenin to the Dlk-1 promoter, leading to upregulation of Dlk-1 and delayed adipogenic conversion. Copr5 KO mice display reduced retroperitoneal white adipose tissue with fewer, larger adipocytes.\",\n      \"method\": \"Copr5 knockout mice, primary MEF culture, embryoid body differentiation, chromatin immunoprecipitation (ChIP), differential transcriptomic analysis\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, ChIP, in vivo and in vitro phenotyping, single lab\",\n      \"pmids\": [\"25681392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Genetic inactivation of Coprs in mice disrupts spermatogonia-to-spermatid maturation. Mass spectrometry after co-immunoprecipitation with anti-Coprs antibody identified Miwi (a Piwi protein) as a Coprs-associated protein in testis. Coprs KO leads to deregulation of Miwi and pachytene pre-piRNA levels and derepression of LINE1 retrotransposons in spermatocytes, implicating COPR5 in Prmt5-mediated genome surveillance via the piRNA pathway.\",\n      \"method\": \"Coprs knockout mice, co-immunoprecipitation with mass spectrometry, LINE1 expression analysis, piRNA profiling\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype, Co-IP/MS for Miwi interaction, single lab\",\n      \"pmids\": [\"30652083\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COPR5/COPRS is a nuclear histone H4-binding adaptor protein that specifically recruits PRMT5 to chromatin via direct interaction with PRMT5's TIM barrel domain (through a GQF[D/E]DA[E/D] motif), modulates PRMT5 substrate specificity toward histone H4-R3 methylation, and coordinates transcriptional programs required for cell cycle control, myogenic differentiation, adipogenesis, and piRNA-mediated retrotransposon silencing in spermatocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COPRS (COPR5) is a nuclear adaptor protein that recruits the arginine methyltransferase PRMT5 to chromatin and shapes its histone substrate specificity, thereby coordinating transcriptional programs underlying cell-cycle control, differentiation, and germline genome surveillance [#0]. It binds directly and specifically to PRMT5 — not other PRMT family members — and also engages the amino terminus of histone H4, and these dual interactions are required to deliver PRMT5 onto nucleosomes, where the COPR5-bound enzyme preferentially methylates histone H4-R3 over histone H3 [#0]. The PRMT5 interaction is mediated by a GQF[D/E]DA[E/D] motif in COPRS that docks onto the PRMT5 TIM-barrel domain, a binding mode shared with the PRMT5 adaptors pICln and RioK1 [#1]. Through this recruitment activity COPRS controls specific target genes: it is needed for PRMT5 loading at the CCNE1 promoter [#0], and during myogenic differentiation it cooperates with the RUNX1–CBFβ complex to target PRMT5 to the p21 and MYOGENIN promoters, driving cell-cycle exit and muscle differentiation [#2]. During adipogenesis it acts as a negative regulator of the Wnt target gene Dlk-1, supporting recruitment of both PRMT5 and β-catenin to the Dlk-1 promoter [#3]. In the male germline COPRS associates with the Piwi protein Miwi and is required for normal piRNA levels and LINE1 retrotransposon repression in spermatocytes, linking it to PRMT5-mediated genome surveillance via the piRNA pathway [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that PRMT5 requires a dedicated adaptor to reach chromatin and to bias its product specificity, answering how a soluble methyltransferase selectively methylates nucleosomal histone H4-R3 at specific genes.\",\n      \"evidence\": \"In vitro binding, reciprocal Co-IP in cells, reconstituted nucleosome methylation, ChIP, and siRNA knockdown at the CCNE1 locus\",\n      \"pmids\": [\"18404153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the COPR5–PRMT5 interaction not yet resolved in this study\",\n        \"Mechanism by which H4 binding redirects specificity toward H4-R3 not defined at atomic resolution\",\n        \"Full repertoire of COPR5-dependent PRMT5 target genes not mapped\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed how the COPR5–PRMT5 complex is targeted to specific promoters and linked it to a developmental program, answering what guides this adaptor to defined loci during differentiation.\",\n      \"evidence\": \"siRNA knockdown in C2C12 myoblasts, ChIP at p21/MYOG promoters, Co-IP with RUNX1–CBFβ, and an in vivo cardiotoxin muscle-injury model\",\n      \"pmids\": [\"22193545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether RUNX1–CBFβ is the sole or general targeting partner is unclear\",\n        \"Direct versus indirect nature of the COPR5–RUNX1 interaction not fully resolved\",\n        \"Single-lab phenotype without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the recruitment paradigm to Wnt-responsive transcription in adipogenesis, answering whether COPR5 also coordinates a non-myogenic differentiation program and a co-recruited transcription factor.\",\n      \"evidence\": \"Copr5 knockout mice and MEFs, embryoid body differentiation, ChIP showing loss of Prmt5 and β-catenin at the Dlk-1 promoter, transcriptomics\",\n      \"pmids\": [\"25681392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether COPR5 directly interacts with β-catenin or recruits it indirectly is unresolved\",\n        \"Mechanism by which COPR5 acts as a negative regulator of Dlk-1 not detailed\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected COPR5 to germline genome surveillance, answering whether its adaptor function extends beyond transcriptional control into the piRNA pathway.\",\n      \"evidence\": \"Coprs knockout mice, Co-IP/mass spectrometry identifying Miwi, piRNA profiling, and LINE1 expression analysis in testis\",\n      \"pmids\": [\"30652083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the Coprs–Miwi association is direct or PRMT5-dependent is not established\",\n        \"Single Co-IP/MS identification without reciprocal validation\",\n        \"Mechanistic link between COPR5 and piRNA biogenesis versus retrotransposon silencing not separated\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the molecular interface of the COPR5–PRMT5 interaction, answering how the adaptor physically docks onto the enzyme and placing it within a shared family of PRMT5 adaptors.\",\n      \"evidence\": \"Peptide truncation/mutation and biochemical binding assays with crystallography of a RioK1-derived comparator peptide on the PRMT5 TIM-barrel domain\",\n      \"pmids\": [\"33624332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No co-crystal structure of the COPR5 peptide itself with PRMT5\",\n        \"Functional consequence of disrupting the GQF[D/E]DA[E/D] motif in cells not tested here\",\n        \"How competing adaptors (pICln, RioK1) are selected at given loci is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COPR5 adaptor choice, locus selection, and H4-R3 specificity are coordinated to switch between distinct transcriptional and germline genome-surveillance programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No integrated model linking adaptor competition to context-specific PRMT5 output\",\n        \"Genome-wide map of COPR5-dependent PRMT5 targets across tissues lacking\",\n        \"Direct structural data for the COPR5–PRMT5 and COPR5–H4 contacts absent\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"COPR5–PRMT5 complex\"],\n    \"partners\": [\"PRMT5\", \"RUNX1\", \"CBFB\", \"MIWI\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}