{"gene":"PF3D7_0519500","run_date":"2026-09-07T10:55:52","timeline":{"discoveries":[{"year":2019,"finding":"PyCCR4-1 (the P. yoelii ortholog of PF3D7_0519500) functions as a putative deadenylase within the CAF1/CCR4/NOT complex and is required for male gametocyte maturation and host-to-vector transmission; deletion or catalytic inactivation of pyccr4-1 causes loss of coordination of male gametocyte maturation and reduced mosquito infectivity.","method":"Genetic knockout and catalytic-dead mutant generation in P. yoelii, comparative RNA-seq of wild-type vs. deletion parasites, circular RT-PCR of bound transcripts, immunoprecipitation of the complex","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO and catalytic-dead mutant with defined cellular phenotypes and RNA-seq, single lab but multiple orthogonal methods","pmids":["30703164"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2019,"finding":"PyCCR4-1 associates with specific gametocyte-expressed mRNAs (some directly co-immunoprecipitated with the complex) and regulates their abundance; deletion of pyccr4-1 does not cause gross changes to the UTR or poly(A) tail length of at least one bound, dysregulated transcript.","method":"Immunoprecipitation of the CCR4-1 complex followed by RNA identification; circular RT-PCR for poly(A) tail length analysis","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP with RNA and circular RT-PCR, single lab, multiple orthogonal methods","pmids":["30703164"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2015,"finding":"PF3D7_0519500 (CCR4-1) is identified bioinformatically as a component of the PfCaf1-CCR4-NOT complex in P. falciparum, with the complex membership inferred from comparative interactome analyses with human and Plasmodium protein-protein interaction datasets.","method":"Bioinformatic/comparative interactome analysis; protein-protein interaction network construction in Cytoscape","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no direct experimental validation of PF3D7_0519500 specifically","pmids":["26525978"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"CCR4-1 (PF3D7_0519500) is a putative deadenylase subunit of the CAF1/CCR4/NOT mRNA regulatory complex in Plasmodium; in P. yoelii, its catalytic activity and gene integrity are required for proper male gametocyte maturation, regulation of specific gametocyte mRNA abundance, and efficient host-to-vector transmission, while its membership in the complex in P. falciparum is supported only by bioinformatic evidence."},"narrative":{"mechanistic_narrative":"CCR4-1 (PF3D7_0519500) is a putative deadenylase subunit of the CAF1/CCR4/NOT complex that couples post-transcriptional mRNA regulation to sexual-stage development in Plasmodium [PMID:30703164]. The functional evidence derives from the P. yoelii ortholog PyCCR4-1, where both gene deletion and catalytic inactivation disrupt the coordination of male gametocyte maturation and reduce mosquito infectivity, establishing that its deadenylase activity is required for efficient host-to-vector transmission [PMID:30703164]. Mechanistically, PyCCR4-1 associates with specific gametocyte-expressed mRNAs, some co-immunoprecipitated directly with the complex, and controls their abundance, yet loss of the protein does not grossly alter the UTR or poly(A) tail length of at least one bound, dysregulated transcript, indicating that its effect on target transcript levels is not explained by bulk poly(A) shortening of those messages [PMID:30703164]. In P. falciparum, CCR4-1 has been placed in the PfCaf1-CCR4-NOT complex only by bioinformatic comparative interactome analysis, with no direct experimental validation of the P. falciparum protein itself [PMID:26525978]. Beyond these findings, the structural basis of its catalysis, the full set of target transcripts, and its precise mechanism within the complex have not been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Before any functional study, it was unknown whether PF3D7_0519500 belonged to a defined regulatory machinery; comparative interactome analysis placed it as a predicted component of the PfCaf1-CCR4-NOT complex, giving the first hypothesis for its cellular context.","evidence":"Bioinformatic/comparative interactome analysis and protein-protein interaction network construction in P. falciparum","pmids":["26525978"],"confidence":"Low","gaps":["Purely computational prediction with no direct experimental validation of PF3D7_0519500 in P. falciparum","Complex membership, stoichiometry, and direct binding partners of the P. falciparum protein not demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"It was unknown whether CCR4-1 has a biological role and whether its putative catalytic activity matters; genetic deletion and a catalytic-dead mutant of the P. yoelii ortholog showed that the protein and its deadenylase activity are required for coordinated male gametocyte maturation and mosquito transmission.","evidence":"Knockout and catalytic-dead mutant generation with phenotypic and transmission analysis in P. yoelii","pmids":["30703164"],"confidence":"Medium","gaps":["Shown in P. yoelii; the P. falciparum ortholog remains functionally untested","Direct demonstration of deadenylase enzymatic activity in vitro not established","Single lab"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2019,"claim":"It was unknown how CCR4-1 exerts its developmental effect; immunoprecipitation identified specific bound gametocyte mRNAs whose abundance it regulates, while poly(A)/UTR analysis showed no gross tail change on a bound transcript, indicating its regulation of those targets does not reduce simply to bulk deadenylation.","evidence":"Complex immunoprecipitation with RNA identification and circular RT-PCR for poly(A) tail length in P. yoelii","pmids":["30703164"],"confidence":"Medium","gaps":["Full complement of directly bound target transcripts not defined","Mechanism linking mRNA binding to abundance changes without poly(A) shortening unresolved","Direct versus indirect association of individual transcripts not fully separated"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":null,"claim":"Whether P. falciparum CCR4-1 is experimentally a functional deadenylase subunit with the same transmission role as its P. yoelii ortholog, and the structural and mechanistic basis of its target regulation within the CAF1/CCR4/NOT complex, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental validation of the P. falciparum protein","No structural model or in vitro enzymatic reconstitution","Mechanism of transcript selection and recruitment to the complex unknown"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["CAF1/CCR4/NOT (CCR4-NOT) complex [#0]","PfCaf1-CCR4-NOT complex (bioinformatically inferred in P. falciparum) [#2]"],"partners":[],"other_free_text":["In P. yoelii, deletion or catalytic inactivation of the ortholog disrupts coordinated male gametocyte maturation and reduces host-to-vector transmission [#0].","Associates with specific gametocyte-expressed mRNAs and regulates their abundance without grossly altering poly(A) tail or UTR of at least one bound transcript [#1].","P. falciparum complex membership of PF3D7_0519500 rests on comparative interactome prediction only, with no direct experimental validation [#2]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"26525978","id":"PMC_26525978","title":"A bioinformatic survey of RNA-binding proteins in Plasmodium.","date":"2015","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/26525978","citation_count":62,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CCR4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20011659","id":"PMC_20011659","title":"Toward the discovery of vaccine adjuvants: coupling in silico screening and in vitro analysis of antagonist binding to human and mouse CCR4 receptors.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20011659","citation_count":51,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CCR4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21803864","id":"PMC_21803864","title":"CCR4-associated factor 1 coordinates the expression of Plasmodium falciparum egress and invasion proteins.","date":"2011","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/21803864","citation_count":36,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CCR4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30703164","id":"PMC_30703164","title":"Plasmodium male gametocyte development and transmission are critically regulated by the two putative deadenylases of the CAF1/CCR4/NOT complex.","date":"2019","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/30703164","citation_count":30,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CCR4-1","CCR4","PyCCR4-1","PyCCR4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31531994","id":"PMC_31531994","title":"The molecular machinery of translational control in malaria parasites.","date":"2019","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31531994","citation_count":28,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CCR4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34673764","id":"PMC_34673764","title":"The Plasmodium NOT1-G paralogue is an essential regulator of sexual stage maturation and parasite transmission.","date":"2021","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/34673764","citation_count":27,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CCR4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5736,"output_tokens":928,"usd":0.015564,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5665,"output_tokens":2190,"usd":0.041537,"stage2_stop_reason":"end_turn"},"total_usd":0.057101,"stage1_batch_id":"msgbatch_01DbiymDmubkPpYvdbAu5a7V","stage2_batch_id":"msgbatch_012TbrWvMRH129T7PQ4SmvrJ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"PyCCR4-1 (the P. yoelii ortholog of PF3D7_0519500) functions as a putative deadenylase within the CAF1/CCR4/NOT complex and is required for male gametocyte maturation and host-to-vector transmission; deletion or catalytic inactivation of pyccr4-1 causes loss of coordination of male gametocyte maturation and reduced mosquito infectivity.\",\n      \"method\": \"Genetic knockout and catalytic-dead mutant generation in P. yoelii, comparative RNA-seq of wild-type vs. deletion parasites, circular RT-PCR of bound transcripts, immunoprecipitation of the complex\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO and catalytic-dead mutant with defined cellular phenotypes and RNA-seq, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30703164\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PyCCR4-1 associates with specific gametocyte-expressed mRNAs (some directly co-immunoprecipitated with the complex) and regulates their abundance; deletion of pyccr4-1 does not cause gross changes to the UTR or poly(A) tail length of at least one bound, dysregulated transcript.\",\n      \"method\": \"Immunoprecipitation of the CCR4-1 complex followed by RNA identification; circular RT-PCR for poly(A) tail length analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP with RNA and circular RT-PCR, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30703164\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PF3D7_0519500 (CCR4-1) is identified bioinformatically as a component of the PfCaf1-CCR4-NOT complex in P. falciparum, with the complex membership inferred from comparative interactome analyses with human and Plasmodium protein-protein interaction datasets.\",\n      \"method\": \"Bioinformatic/comparative interactome analysis; protein-protein interaction network construction in Cytoscape\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no direct experimental validation of PF3D7_0519500 specifically\",\n      \"pmids\": [\"26525978\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"CCR4-1 (PF3D7_0519500) is a putative deadenylase subunit of the CAF1/CCR4/NOT mRNA regulatory complex in Plasmodium; in P. yoelii, its catalytic activity and gene integrity are required for proper male gametocyte maturation, regulation of specific gametocyte mRNA abundance, and efficient host-to-vector transmission, while its membership in the complex in P. falciparum is supported only by bioinformatic evidence.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCR4-1 (PF3D7_0519500) is a putative deadenylase subunit of the CAF1/CCR4/NOT complex that couples post-transcriptional mRNA regulation to sexual-stage development in Plasmodium [#0]. The functional evidence derives from the P. yoelii ortholog PyCCR4-1, where both gene deletion and catalytic inactivation disrupt the coordination of male gametocyte maturation and reduce mosquito infectivity, establishing that its deadenylase activity is required for efficient host-to-vector transmission [#0]. Mechanistically, PyCCR4-1 associates with specific gametocyte-expressed mRNAs, some co-immunoprecipitated directly with the complex, and controls their abundance, yet loss of the protein does not grossly alter the UTR or poly(A) tail length of at least one bound, dysregulated transcript, indicating that its effect on target transcript levels is not explained by bulk poly(A) shortening of those messages [#1]. In P. falciparum, CCR4-1 has been placed in the PfCaf1-CCR4-NOT complex only by bioinformatic comparative interactome analysis, with no direct experimental validation of the P. falciparum protein itself [#2]. Beyond these findings, the structural basis of its catalysis, the full set of target transcripts, and its precise mechanism within the complex have not been characterized in the available corpus.\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Before any functional study, it was unknown whether PF3D7_0519500 belonged to a defined regulatory machinery; comparative interactome analysis placed it as a predicted component of the PfCaf1-CCR4-NOT complex, giving the first hypothesis for its cellular context.\",\n      \"evidence\": \"Bioinformatic/comparative interactome analysis and protein-protein interaction network construction in P. falciparum\",\n      \"pmids\": [\"26525978\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Purely computational prediction with no direct experimental validation of PF3D7_0519500 in P. falciparum\",\n        \"Complex membership, stoichiometry, and direct binding partners of the P. falciparum protein not demonstrated\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unknown whether CCR4-1 has a biological role and whether its putative catalytic activity matters; genetic deletion and a catalytic-dead mutant of the P. yoelii ortholog showed that the protein and its deadenylase activity are required for coordinated male gametocyte maturation and mosquito transmission.\",\n      \"evidence\": \"Knockout and catalytic-dead mutant generation with phenotypic and transmission analysis in P. yoelii\",\n      \"pmids\": [\"30703164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Shown in P. yoelii; the P. falciparum ortholog remains functionally untested\",\n        \"Direct demonstration of deadenylase enzymatic activity in vitro not established\",\n        \"Single lab\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unknown how CCR4-1 exerts its developmental effect; immunoprecipitation identified specific bound gametocyte mRNAs whose abundance it regulates, while poly(A)/UTR analysis showed no gross tail change on a bound transcript, indicating its regulation of those targets does not reduce simply to bulk deadenylation.\",\n      \"evidence\": \"Complex immunoprecipitation with RNA identification and circular RT-PCR for poly(A) tail length in P. yoelii\",\n      \"pmids\": [\"30703164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Full complement of directly bound target transcripts not defined\",\n        \"Mechanism linking mRNA binding to abundance changes without poly(A) shortening unresolved\",\n        \"Direct versus indirect association of individual transcripts not fully separated\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether P. falciparum CCR4-1 is experimentally a functional deadenylase subunit with the same transmission role as its P. yoelii ortholog, and the structural and mechanistic basis of its target regulation within the CAF1/CCR4/NOT complex, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No experimental validation of the P. falciparum protein\",\n        \"No structural model or in vitro enzymatic reconstitution\",\n        \"Mechanism of transcript selection and recruitment to the complex unknown\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004535\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003730\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0000289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0006402\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"CAF1/CCR4/NOT (CCR4-NOT) complex [#0]\",\n      \"PfCaf1-CCR4-NOT complex (bioinformatically inferred in P. falciparum) [#2]\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"In P. yoelii, deletion or catalytic inactivation of the ortholog disrupts coordinated male gametocyte maturation and reduces host-to-vector transmission [#0].\",\n      \"Associates with specific gametocyte-expressed mRNAs and regulates their abundance without grossly altering poly(A) tail or UTR of at least one bound transcript [#1].\",\n      \"P. falciparum complex membership of PF3D7_0519500 rests on comparative interactome prediction only, with no direct experimental validation [#2].\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0519500","name":null,"product":"CCR4 domain-containing protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1234300","name":null,"product":"CCR4 domain-containing protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1013600","name":null,"product":"CCR4 domain-containing protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"CCR4-1","evaluation":null}