{"gene":"PF3D7_0811300","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2011,"finding":"CAF1 (PF3D7_0811300) knockout in P. falciparum causes mistimed expression, aberrant accumulation, and mislocalization of proteins involved in parasite egress and invasion, leading to premature release of predominantly half-finished merozoites and drastically reduced intraerythrocytic growth rate; CAF1 was shown to regulate more than 1,000 genes during asexual blood-stage development, particularly egress and invasion genes.","method":"Genetic knockout with phenotypic analysis (growth rate, protein localization, merozoite morphology) and transcriptomic profiling","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal readouts (transcriptomics, protein localization, growth phenotype) in a single focused study on this specific gene","pmids":["21803864"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"CAF1 (PF3D7_0811300) is a component of the CCR4-NOT complex in P. falciparum and functions as a significant gene regulatory mechanism required for intraerythrocytic development.","method":"Genetic knockout and comparative interactome analysis","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct KO study with pathway placement within CCR4-NOT complex, single lab","pmids":["21803864"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"Expression of only the N-terminal CAF1 deadenylase domain of the essential CAF1 protein in P. yoelii leads to loss of initial coordination of male gametocyte maturation and reduction of parasite infectivity of the mosquito, phenocopying deletion of PyCCR4-1; this places CAF1's catalytic deadenylase domain as functionally required for male gametocyte development and transmission.","method":"Domain-truncation expression construct (N-terminal CAF1 domain only) with phenotypic analysis of male gametocyte maturation and mosquito infectivity","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-truncation functional experiment with transmission phenotype readout, single lab, single study","pmids":["30703164"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2015,"finding":"Comparative interactome analysis suggests conservation of the PfCaf1-CCR4-NOT complex in P. falciparum, with CAF1 (PF3D7_0811300) predicted to participate in an interaction network analogous to that in human cells; no direct experimental validation was performed in this study.","method":"Bioinformatic/interactome network analysis using Cytoscape; computational prediction only","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no direct experimental validation of CAF1 interactions in this paper","pmids":["26525978"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"CAF1 (PF3D7_0811300), a component of the CCR4-NOT deadenylase complex in Plasmodium, is essential for coordinated gene regulation during intraerythrocytic development in P. falciparum—where its loss causes mistimed expression and mislocalization of egress/invasion proteins and premature merozoite release—and its N-terminal deadenylase domain is required for male gametocyte maturation and host-to-vector transmission in P. yoelii."},"narrative":{"mechanistic_narrative":"CAF1 (PF3D7_0811300) is a component of the CCR4-NOT deadenylase complex in Plasmodium and acts as a major post-transcriptional regulator coordinating the timing of gene expression during parasite development [PMID:21803864]. In P. falciparum, CAF1 governs the expression of more than 1,000 genes across asexual blood-stage development, most prominently those controlling egress and invasion; its loss causes mistimed expression, aberrant accumulation, and mislocalization of egress/invasion proteins, producing premature release of half-finished merozoites and severely reduced intraerythrocytic growth [PMID:21803864]. In P. yoelii, expression of only the N-terminal deadenylase domain of CAF1 uncouples the initial coordination of male gametocyte maturation and reduces mosquito infectivity, phenocopying loss of the CCR4-1 subunit and establishing the catalytic deadenylase domain as required for male gametocyte development and host-to-vector transmission [PMID:30703164]. Beyond its role as a CCR4-NOT subunit driving timed mRNA regulation in these two contexts, no further biochemical detail—such as direct target mRNAs or reconstituted enzymatic activity—has been characterized for PF3D7_0811300 in the available corpus.","teleology":[{"year":2011,"claim":"Established that CAF1 is not merely a housekeeping factor but a central timekeeper of blood-stage gene expression, resolving whether post-transcriptional regulation via CCR4-NOT controls the egress/invasion program.","evidence":"Genetic knockout in P. falciparum with transcriptomic profiling, protein localization, and merozoite morphology/growth-rate readouts","pmids":["21803864"],"confidence":"High","gaps":["Direct mRNA targets bound or deadenylated by CAF1 not identified","Whether the phenotype reflects CAF1 catalytic activity or a scaffolding role within CCR4-NOT was not separated","No structural or biochemical demonstration of deadenylase activity for the P. falciparum protein"],"attribution":[]},{"year":2011,"claim":"Placed CAF1 within the CCR4-NOT complex in P. falciparum, positioning it in a defined regulatory pathway rather than acting in isolation.","evidence":"Genetic knockout combined with comparative interactome analysis in P. falciparum","pmids":["21803864"],"confidence":"Medium","gaps":["Direct physical interactions with other CCR4-NOT subunits not experimentally mapped in this study","Stoichiometry and architecture of the Plasmodium complex undefined"],"attribution":[]},{"year":2015,"claim":"Tested whether the CAF1-CCR4-NOT complex architecture is conserved in P. falciparum, offering a predicted interaction network analogous to the human complex.","evidence":"Bioinformatic interactome/network analysis (Cytoscape); computational prediction only in P. falciparum","pmids":["26525978"],"confidence":"Low","gaps":["Prediction only, with no direct experimental validation of CAF1 interactions","Analogy to human complex not tested biochemically in the parasite"],"attribution":[]},{"year":2019,"claim":"Determined that CAF1's catalytic N-terminal deadenylase domain is functionally required for sexual-stage development and transmission, extending its role beyond asexual growth.","evidence":"Domain-truncation expression construct (N-terminal deadenylase domain only) in P. yoelii with male gametocyte maturation and mosquito infectivity readouts","pmids":["30703164"],"confidence":"Medium","gaps":["Direct measurement of deadenylase enzymatic activity not shown","mRNA targets in male gametocytes not identified","Mechanistic link between the domain and CCR4-1 phenocopy not resolved at the molecular level"],"attribution":[]},{"year":null,"claim":"The direct mRNA substrates of CAF1, its enzymatic deadenylase activity in vitro, and the physical architecture of the Plasmodium CCR4-NOT complex remain uncharacterized.","evidence":"No discovery in the corpus provides target identification, reconstituted activity, or experimentally resolved complex structure","pmids":[],"confidence":"Low","gaps":["No direct target mRNAs identified","No reconstituted deadenylase assay for PF3D7_0811300","Complex composition and subunit contacts experimentally unmapped"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["CCR4-NOT complex"],"partners":["CCR4-1 (P. YOELII, PHENOCOPY RELATIONSHIP)"],"other_free_text":["Knockout in P. falciparum dysregulates >1,000 genes, prominently egress and invasion genes, causing premature release of half-finished merozoites [#0]","N-terminal deadenylase domain required for male gametocyte maturation and mosquito transmission in P. yoelii [#2]","CCR4-NOT complex conservation in P. falciparum supported only by computational prediction [#3]"]}},"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":["CAF1","CCR4","PfCAF1"],"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":["CAF1","CCR4-associated factor 1","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":["CAF1","CCR4","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":["CAF1","CCR4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29183721","id":"PMC_29183721","title":"Role of Chromatin assembly factor 1 in DNA replication of Plasmodium falciparum.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29183721","citation_count":8,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CAF1","PfCAF1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32363442","id":"PMC_32363442","title":"The multifaceted histone chaperone RbAp46/48 in Plasmodium falciparum: structural insights, production, and characterization.","date":"2020","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/32363442","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CAF1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6126,"output_tokens":1447,"usd":0.020042,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5930,"output_tokens":2007,"usd":0.039912,"stage2_stop_reason":"end_turn"},"total_usd":0.059954,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully distinguish between papers about PF3D7_0811300 (CAF1, the CCR4-associated factor 1, a deadenylase component of the CCR4-NOT complex) and other genes that share similar names:\n\n- Paper [2]: Directly about PF3D7_0811300 CAF1 in P. falciparum → INCLUDE\n- Paper [3]: About PyCCR4-1 and CAF1 domain in P. yoelii → INCLUDE (mentions CAF1 domain function)\n- Paper [1]: Bioinformatic survey mentioning PfCaf1-CCR4-NOT complex → minimal mechanistic content about this specific gene\n- Paper [5]: About NOT1-G paralogue, mentions CAF1/CCR4/Not complex context → only tangentially about CAF1\n- Paper [4]: Review about translational control, mentions Ccr4-Not → no direct mechanistic experiments on CAF1\n- Paper [6]: About \"chromatin assembly factor 1\" (PfCAF1) — this is a DIFFERENT protein (chromatin assembly factor, not CCR4-associated factor). The gene ID PF3D7_0811300 is the CCR4-associated factor 1, not the chromatin assembly factor. → EXCLUDE (alias collision with a different gene)\n- Paper [7]: About RbAp46/48 and CAF-1 chromatin complex → EXCLUDE (different protein)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"CAF1 (PF3D7_0811300) knockout in P. falciparum causes mistimed expression, aberrant accumulation, and mislocalization of proteins involved in parasite egress and invasion, leading to premature release of predominantly half-finished merozoites and drastically reduced intraerythrocytic growth rate; CAF1 was shown to regulate more than 1,000 genes during asexual blood-stage development, particularly egress and invasion genes.\",\n      \"method\": \"Genetic knockout with phenotypic analysis (growth rate, protein localization, merozoite morphology) and transcriptomic profiling\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal readouts (transcriptomics, protein localization, growth phenotype) in a single focused study on this specific gene\",\n      \"pmids\": [\"21803864\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CAF1 (PF3D7_0811300) is a component of the CCR4-NOT complex in P. falciparum and functions as a significant gene regulatory mechanism required for intraerythrocytic development.\",\n      \"method\": \"Genetic knockout and comparative interactome analysis\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct KO study with pathway placement within CCR4-NOT complex, single lab\",\n      \"pmids\": [\"21803864\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Expression of only the N-terminal CAF1 deadenylase domain of the essential CAF1 protein in P. yoelii leads to loss of initial coordination of male gametocyte maturation and reduction of parasite infectivity of the mosquito, phenocopying deletion of PyCCR4-1; this places CAF1's catalytic deadenylase domain as functionally required for male gametocyte development and transmission.\",\n      \"method\": \"Domain-truncation expression construct (N-terminal CAF1 domain only) with phenotypic analysis of male gametocyte maturation and mosquito infectivity\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-truncation functional experiment with transmission phenotype readout, single lab, single study\",\n      \"pmids\": [\"30703164\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Comparative interactome analysis suggests conservation of the PfCaf1-CCR4-NOT complex in P. falciparum, with CAF1 (PF3D7_0811300) predicted to participate in an interaction network analogous to that in human cells; no direct experimental validation was performed in this study.\",\n      \"method\": \"Bioinformatic/interactome network analysis using Cytoscape; computational prediction only\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no direct experimental validation of CAF1 interactions in this paper\",\n      \"pmids\": [\"26525978\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"CAF1 (PF3D7_0811300), a component of the CCR4-NOT deadenylase complex in Plasmodium, is essential for coordinated gene regulation during intraerythrocytic development in P. falciparum—where its loss causes mistimed expression and mislocalization of egress/invasion proteins and premature merozoite release—and its N-terminal deadenylase domain is required for male gametocyte maturation and host-to-vector transmission in P. yoelii.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CAF1 (PF3D7_0811300) is a component of the CCR4-NOT deadenylase complex in Plasmodium and acts as a major post-transcriptional regulator coordinating the timing of gene expression during parasite development [#0, #1]. In P. falciparum, CAF1 governs the expression of more than 1,000 genes across asexual blood-stage development, most prominently those controlling egress and invasion; its loss causes mistimed expression, aberrant accumulation, and mislocalization of egress/invasion proteins, producing premature release of half-finished merozoites and severely reduced intraerythrocytic growth [#0]. In P. yoelii, expression of only the N-terminal deadenylase domain of CAF1 uncouples the initial coordination of male gametocyte maturation and reduces mosquito infectivity, phenocopying loss of the CCR4-1 subunit and establishing the catalytic deadenylase domain as required for male gametocyte development and host-to-vector transmission [#2]. Beyond its role as a CCR4-NOT subunit driving timed mRNA regulation in these two contexts, no further biochemical detail—such as direct target mRNAs or reconstituted enzymatic activity—has been characterized for PF3D7_0811300 in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that CAF1 is not merely a housekeeping factor but a central timekeeper of blood-stage gene expression, resolving whether post-transcriptional regulation via CCR4-NOT controls the egress/invasion program.\",\n      \"evidence\": \"Genetic knockout in P. falciparum with transcriptomic profiling, protein localization, and merozoite morphology/growth-rate readouts\",\n      \"pmids\": [\"21803864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mRNA targets bound or deadenylated by CAF1 not identified\", \"Whether the phenotype reflects CAF1 catalytic activity or a scaffolding role within CCR4-NOT was not separated\", \"No structural or biochemical demonstration of deadenylase activity for the P. falciparum protein\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed CAF1 within the CCR4-NOT complex in P. falciparum, positioning it in a defined regulatory pathway rather than acting in isolation.\",\n      \"evidence\": \"Genetic knockout combined with comparative interactome analysis in P. falciparum\",\n      \"pmids\": [\"21803864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interactions with other CCR4-NOT subunits not experimentally mapped in this study\", \"Stoichiometry and architecture of the Plasmodium complex undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tested whether the CAF1-CCR4-NOT complex architecture is conserved in P. falciparum, offering a predicted interaction network analogous to the human complex.\",\n      \"evidence\": \"Bioinformatic interactome/network analysis (Cytoscape); computational prediction only in P. falciparum\",\n      \"pmids\": [\"26525978\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Prediction only, with no direct experimental validation of CAF1 interactions\", \"Analogy to human complex not tested biochemically in the parasite\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Determined that CAF1's catalytic N-terminal deadenylase domain is functionally required for sexual-stage development and transmission, extending its role beyond asexual growth.\",\n      \"evidence\": \"Domain-truncation expression construct (N-terminal deadenylase domain only) in P. yoelii with male gametocyte maturation and mosquito infectivity readouts\",\n      \"pmids\": [\"30703164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct measurement of deadenylase enzymatic activity not shown\", \"mRNA targets in male gametocytes not identified\", \"Mechanistic link between the domain and CCR4-1 phenocopy not resolved at the molecular level\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct mRNA substrates of CAF1, its enzymatic deadenylase activity in vitro, and the physical architecture of the Plasmodium CCR4-NOT complex remain uncharacterized.\",\n      \"evidence\": \"No discovery in the corpus provides target identification, reconstituted activity, or experimentally resolved complex structure\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct target mRNAs identified\", \"No reconstituted deadenylase assay for PF3D7_0811300\", \"Complex composition and subunit contacts experimentally unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004535\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0000289\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0010608\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"CCR4-NOT complex\"],\n    \"partners\": [\"CCR4-1 (P. yoelii, phenocopy relationship)\"],\n    \"other_free_text\": [\n      \"Knockout in P. falciparum dysregulates >1,000 genes, prominently egress and invasion genes, causing premature release of half-finished merozoites [#0]\",\n      \"N-terminal deadenylase domain required for male gametocyte maturation and mosquito transmission in P. yoelii [#2]\",\n      \"CCR4-NOT complex conservation in P. falciparum supported only by computational prediction [#3]\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0811300","name":null,"product":"CCR4-associated factor 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1426200","name":null,"product":"CCR4-associated factor 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1429400","name":null,"product":"CCR4-associated factor 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"CAF1","evaluation":null}