{"gene":"PF3D7_1422800","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2020,"finding":"Conditional knockdown of ARP4 (PF3D7_1422800) in P. falciparum inhibited blood-stage parasite development, establishing that ARP4 is essential for the intraerythrocytic cell cycle.","method":"glmS ribozyme-based conditional knockdown (CRISPR-Cas9 tagging) combined with growth curve assay and western blot","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean inducible knockdown with defined growth phenotype, single lab, two orthogonal readouts (growth curve + WB)","pmids":["32552779"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"ARP4 (PF3D7_1422800) localizes to the nucleus of P. falciparum blood-stage parasites and co-localizes with ARP6, as demonstrated by co-immunofluorescence assay.","method":"Co-immunofluorescence assay (co-IFA) on transgenic parasites expressing tagged ARP4 and ARP6","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by co-IFA, single lab, supported by co-IP","pmids":["32552779"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"ARP4 (PF3D7_1422800) directly interacts with ARP6 in P. falciparum, as validated by co-immunoprecipitation.","method":"Co-immunoprecipitation (co-IP) from transgenic parasite lines expressing epitope-tagged ARP4 and ARP6","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP experiment, single lab, corroborated by co-IFA","pmids":["32552779"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"ARP4 (PF3D7_1422800) co-localizes with histone variant H2A.Z and euchromatic marker H3K9ac at intergenic/upstream regions of euchromatic genes, and its knockdown causes depletion of H2A.Z and reduced H3K9ac at those regions, repressing transcription of H2A.Z-dependent genes.","method":"ChIP-seq for H2A.Z and H3K9ac in ARP4 knockdown vs. control parasites; RNA-seq for transcriptomic changes","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal genome-wide methods (ChIP-seq + RNA-seq) in inducible knockdown, single lab","pmids":["32552779"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"ARP4 (PF3D7_1422800) was identified as a component of the P. falciparum NuA4 (PfNuA4) complex by tandem affinity purification of PfMYST followed by LC-MS/MS, consistent with its role as the homolog of yeast ARP4, a shared subunit between the NuA4 and SWR1 complexes.","method":"Tandem affinity purification (TAP) of PfMYST from nuclear extracts followed by LC-MS/MS; reciprocal pulldown of PfEAF2::GFP with GFP-trap beads + LC-MS/MS","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldowns with MS identification, single lab, multiple replicates","pmids":["38564734"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]}],"current_model":"ARP4 (PF3D7_1422800) is a nuclear actin-related protein in P. falciparum that is essential for blood-stage parasite development; it interacts with ARP6 and is a component of the PfNuA4 chromatin-remodeling complex, where it promotes H2A.Z deposition and H3K9ac maintenance at euchromatic gene promoters, thereby supporting transcription of H2A.Z-dependent genes and normal cell-cycle progression."},"narrative":{"mechanistic_narrative":"ARP4 (PF3D7_1422800) is a nuclear actin-related protein of Plasmodium falciparum that couples chromatin remodeling to blood-stage cell-cycle progression [PMID:32552779]. It localizes to the parasite nucleus, where it co-localizes with and directly binds ARP6 [PMID:32552779], and it is a component of the P. falciparum NuA4 (PfNuA4) histone acetyltransferase complex, identified through tandem affinity purification of PfMYST [PMID:38564734]. At intergenic/upstream regions of euchromatic genes ARP4 co-occupies chromatin with the histone variant H2A.Z and the active mark H3K9ac; conditional knockdown depletes H2A.Z and reduces H3K9ac at these regions and represses transcription of H2A.Z-dependent genes, linking ARP4 to maintenance of euchromatic promoter states [PMID:32552779]. Conditional knockdown blocks intraerythrocytic development, establishing ARP4 as essential for the blood-stage cell cycle [PMID:32552779]. Beyond these findings, the biochemical activity of ARP4 within PfNuA4 has not been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Whether ARP4 has a required function in the malaria parasite was unknown; conditional depletion established it as essential for intraerythrocytic development.","evidence":"glmS ribozyme conditional knockdown with growth curves and western blot in P. falciparum blood stages","pmids":["32552779"],"confidence":"Medium","gaps":["Does not define the cell-cycle stage at which arrest occurs","Does not distinguish direct chromatin roles from indirect effects on growth"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"The subcellular context and physical partners of ARP4 were undefined; imaging and pulldown placed it in the nucleus in complex with ARP6.","evidence":"Co-immunofluorescence and co-immunoprecipitation of epitope-tagged ARP4 and ARP6 in transgenic parasites","pmids":["32552779"],"confidence":"Medium","gaps":["Single co-IP without reciprocal validation for the ARP4-ARP6 pair","Stoichiometry and directness of the interaction not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"How ARP4 acts on chromatin was unknown; genome-wide profiling tied it to H2A.Z deposition, H3K9ac maintenance, and transcription of H2A.Z-dependent genes.","evidence":"ChIP-seq for H2A.Z and H3K9ac plus RNA-seq comparing ARP4 knockdown and control parasites","pmids":["32552779"],"confidence":"Medium","gaps":["Whether ARP4 directly drives H2A.Z deposition or acts through a remodeling complex is not established","Enzymatic contribution of ARP4 itself not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"The complex membership of ARP4 was clarified by placing it within the PfNuA4 histone acetyltransferase complex.","evidence":"Tandem affinity purification of PfMYST with LC-MS/MS and reciprocal PfEAF2::GFP pulldown in P. falciparum 3D7","pmids":["38564734"],"confidence":"Medium","gaps":["Does not resolve whether ARP4 also partitions into a SWR1-type complex in the parasite","Functional contribution of ARP4 to PfNuA4 acetyltransferase activity not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":null,"claim":"The biochemical role of ARP4 within PfNuA4 and its mechanistic link between ARP6/H2A.Z chromatin function and NuA4 remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ARP4 within PfNuA4","Whether ARP4 bridges NuA4 and an H2A.Z-depositing remodeler is untested","No defined enzymatic or scaffolding activity for ARP4 itself"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PfNuA4 histone acetyltransferase complex"],"partners":["ARP6","PFMYST","PFEAF2","HISTONE VARIANT H2A.Z"],"other_free_text":["Essential for P. falciparum intraerythrocytic (blood-stage) development [#0]","Knockdown depletes H2A.Z and reduces H3K9ac at euchromatic promoter/upstream regions and represses H2A.Z-dependent genes [#3]","Identified as the P. falciparum homolog of yeast ARP4 [#4]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"32552779","id":"PMC_32552779","title":"Actin-related protein Arp4 regulates euchromatic gene expression and development through H2A.Z deposition in blood-stage Plasmodium falciparum.","date":"2020","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/32552779","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARP4","actin-related protein ARP4","PfARP4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38564734","id":"","title":"MYST regulates DNA repair and forms a NuA4-like complex in the malaria parasite Plasmodium falciparum.","date":"2024","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/38564734","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARP4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33488567","id":"","title":"Optimization of CRISPR/Cas System for Improving Genome Editing Efficiency in Plasmodium falciparum.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33488567","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARP4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38012191","id":"","title":"Genomic analysis of Plasmodium vivax describes patterns of connectivity and putative drivers of adaptation in Ethiopia.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38012191","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARP4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28256794","id":"","title":"Laser capture microdissection enables transcriptomic analysis of dividing and quiescent liver stages of Plasmodium relapsing species.","date":"2017","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28256794","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARP4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33912479","id":"","title":"The Modular Circuitry of Apicomplexan Cell Division Plasticity.","date":"2021","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33912479","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARP4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23060959","id":"","title":"Plasmodium falciparum RuvB proteins: Emerging importance and expectations beyond cell cycle progression.","date":"2012","source":"Communicative & integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/23060959","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARP4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11444,"output_tokens":1351,"usd":0.027298,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6223,"output_tokens":2034,"usd":0.040982,"stage2_stop_reason":"end_turn"},"total_usd":0.06828,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional knockdown of ARP4 (PF3D7_1422800) in P. falciparum inhibited blood-stage parasite development, establishing that ARP4 is essential for the intraerythrocytic cell cycle.\",\n      \"method\": \"glmS ribozyme-based conditional knockdown (CRISPR-Cas9 tagging) combined with growth curve assay and western blot\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean inducible knockdown with defined growth phenotype, single lab, two orthogonal readouts (growth curve + WB)\",\n      \"pmids\": [\"32552779\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARP4 (PF3D7_1422800) localizes to the nucleus of P. falciparum blood-stage parasites and co-localizes with ARP6, as demonstrated by co-immunofluorescence assay.\",\n      \"method\": \"Co-immunofluorescence assay (co-IFA) on transgenic parasites expressing tagged ARP4 and ARP6\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by co-IFA, single lab, supported by co-IP\",\n      \"pmids\": [\"32552779\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARP4 (PF3D7_1422800) directly interacts with ARP6 in P. falciparum, as validated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation (co-IP) from transgenic parasite lines expressing epitope-tagged ARP4 and ARP6\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP experiment, single lab, corroborated by co-IFA\",\n      \"pmids\": [\"32552779\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARP4 (PF3D7_1422800) co-localizes with histone variant H2A.Z and euchromatic marker H3K9ac at intergenic/upstream regions of euchromatic genes, and its knockdown causes depletion of H2A.Z and reduced H3K9ac at those regions, repressing transcription of H2A.Z-dependent genes.\",\n      \"method\": \"ChIP-seq for H2A.Z and H3K9ac in ARP4 knockdown vs. control parasites; RNA-seq for transcriptomic changes\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal genome-wide methods (ChIP-seq + RNA-seq) in inducible knockdown, single lab\",\n      \"pmids\": [\"32552779\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARP4 (PF3D7_1422800) was identified as a component of the P. falciparum NuA4 (PfNuA4) complex by tandem affinity purification of PfMYST followed by LC-MS/MS, consistent with its role as the homolog of yeast ARP4, a shared subunit between the NuA4 and SWR1 complexes.\",\n      \"method\": \"Tandem affinity purification (TAP) of PfMYST from nuclear extracts followed by LC-MS/MS; reciprocal pulldown of PfEAF2::GFP with GFP-trap beads + LC-MS/MS\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldowns with MS identification, single lab, multiple replicates\",\n      \"pmids\": [\"38564734\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    }\n  ],\n  \"current_model\": \"ARP4 (PF3D7_1422800) is a nuclear actin-related protein in P. falciparum that is essential for blood-stage parasite development; it interacts with ARP6 and is a component of the PfNuA4 chromatin-remodeling complex, where it promotes H2A.Z deposition and H3K9ac maintenance at euchromatic gene promoters, thereby supporting transcription of H2A.Z-dependent genes and normal cell-cycle progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARP4 (PF3D7_1422800) is a nuclear actin-related protein of Plasmodium falciparum that couples chromatin remodeling to blood-stage cell-cycle progression [#0, #3]. It localizes to the parasite nucleus, where it co-localizes with and directly binds ARP6 [#1, #2], and it is a component of the P. falciparum NuA4 (PfNuA4) histone acetyltransferase complex, identified through tandem affinity purification of PfMYST [#4]. At intergenic/upstream regions of euchromatic genes ARP4 co-occupies chromatin with the histone variant H2A.Z and the active mark H3K9ac; conditional knockdown depletes H2A.Z and reduces H3K9ac at these regions and represses transcription of H2A.Z-dependent genes, linking ARP4 to maintenance of euchromatic promoter states [#3]. Conditional knockdown blocks intraerythrocytic development, establishing ARP4 as essential for the blood-stage cell cycle [#0]. Beyond these findings, the biochemical activity of ARP4 within PfNuA4 has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether ARP4 has a required function in the malaria parasite was unknown; conditional depletion established it as essential for intraerythrocytic development.\",\n      \"evidence\": \"glmS ribozyme conditional knockdown with growth curves and western blot in P. falciparum blood stages\",\n      \"pmids\": [\"32552779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the cell-cycle stage at which arrest occurs\", \"Does not distinguish direct chromatin roles from indirect effects on growth\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The subcellular context and physical partners of ARP4 were undefined; imaging and pulldown placed it in the nucleus in complex with ARP6.\",\n      \"evidence\": \"Co-immunofluorescence and co-immunoprecipitation of epitope-tagged ARP4 and ARP6 in transgenic parasites\",\n      \"pmids\": [\"32552779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP without reciprocal validation for the ARP4-ARP6 pair\", \"Stoichiometry and directness of the interaction not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"How ARP4 acts on chromatin was unknown; genome-wide profiling tied it to H2A.Z deposition, H3K9ac maintenance, and transcription of H2A.Z-dependent genes.\",\n      \"evidence\": \"ChIP-seq for H2A.Z and H3K9ac plus RNA-seq comparing ARP4 knockdown and control parasites\",\n      \"pmids\": [\"32552779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ARP4 directly drives H2A.Z deposition or acts through a remodeling complex is not established\", \"Enzymatic contribution of ARP4 itself not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The complex membership of ARP4 was clarified by placing it within the PfNuA4 histone acetyltransferase complex.\",\n      \"evidence\": \"Tandem affinity purification of PfMYST with LC-MS/MS and reciprocal PfEAF2::GFP pulldown in P. falciparum 3D7\",\n      \"pmids\": [\"38564734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve whether ARP4 also partitions into a SWR1-type complex in the parasite\", \"Functional contribution of ARP4 to PfNuA4 acetyltransferase activity not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical role of ARP4 within PfNuA4 and its mechanistic link between ARP6/H2A.Z chromatin function and NuA4 remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ARP4 within PfNuA4\", \"Whether ARP4 bridges NuA4 and an H2A.Z-depositing remodeler is untested\", \"No defined enzymatic or scaffolding activity for ARP4 itself\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006338\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0006355\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"PfNuA4 histone acetyltransferase complex\"],\n    \"partners\": [\"ARP6\", \"PfMYST\", \"PfEAF2\", \"histone variant H2A.Z\"],\n    \"other_free_text\": [\n      \"Essential for P. falciparum intraerythrocytic (blood-stage) development [#0]\",\n      \"Knockdown depletes H2A.Z and reduces H3K9ac at euchromatic promoter/upstream regions and represses H2A.Z-dependent genes [#3]\",\n      \"Identified as the P. falciparum homolog of yeast ARP4 [#4]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1422800","name":null,"product":"actin-related protein ARP4","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1020600","name":null,"product":"actin-related protein ARP4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1335200","name":null,"product":"actin-related protein ARP4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ARP4","evaluation":null}