{"gene":"PF3D7_1224500","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2021,"finding":"The N-terminal histone chaperone domain of PfAsf1 (residues 1–159) was solved by X-ray crystallography at 2.4 Å resolution, revealing a beta-sandwich immunoglobulin-like fold with a surface-charge distribution distinct from yeast and human Asf1 despite conserved core structure.","method":"X-ray crystallography","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at 2.4 Å with functional validation, single lab but multiple orthogonal methods","pmids":["33501928"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"PfAsf1 was found to exist in a dimeric state in solution, distinct from the monomeric forms of yeast and human Asf1, as confirmed by solution cross-linking experiments, and the dimerization interface was shown to be variable relative to the conserved histone-interacting surface.","method":"Solution cross-linking experiment","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — crystal structure suggested dimer, confirmed by cross-linking, single lab","pmids":["33501928"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"PfAsf1 specifically interacts with Plasmodium histone H3 and H4, and is able to deposit the H3/H4 dimer onto a DNA template to form disomes, demonstrating histone chaperone activity in chromatin assembly.","method":"In vitro histone deposition assay (disome formation on DNA template); interaction confirmed by pulldown/binding assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of nucleosome assembly activity with substrate specificity confirmed, single lab with multiple orthogonal methods","pmids":["33501928"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"Critical residues of PfAsf1 involved in histone H3/H4 interaction were identified and confirmed by site-directed mutagenesis, establishing the molecular basis of its histone-binding activity.","method":"Site-directed mutagenesis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with functional readout, single lab but rigorous mechanistic approach","pmids":["33501928"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"Computational sequence analysis and integration of high-throughput datasets (RNAi knockdowns, genetic and protein interaction maps, cell-cycle gene expression) predicted that PfAsf1 participates in the conserved histone-loading Hir-Asf1 complex and is involved in chromatin dynamics related to schizogony in Plasmodium; the Hpc2p homolog (containing the HUN domain) is proposed to recruit this complex to lineage-specific chromatin reorganization processes.","method":"Protein sequence profile analysis; integration of high-throughput RNAi, genetic interaction, and cell-cycle expression datasets","journal":"Molecular bioSystems","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational and data-integration inference with no direct biochemical experiment on PfAsf1 itself","pmids":["19225618"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfAsf1 (PF3D7_1224500) is a histone chaperone whose N-terminal domain adopts an immunoglobulin-like beta-sandwich fold and forms a dimer (distinct from yeast/human Asf1); it directly binds Plasmodium histones H3 and H4 through conserved, mutagenesis-validated residues and deposits H3/H4 dimers onto DNA to form disomes, mediating chromatin assembly throughout the P. falciparum life cycle."},"narrative":{"mechanistic_narrative":"PF3D7_1224500 (PfAsf1) is a histone chaperone that mediates chromatin assembly in Plasmodium falciparum by binding histones H3 and H4 and depositing H3/H4 dimers onto DNA to form disomes [PMID:33501928]. Its N-terminal histone chaperone domain (residues 1–159) adopts a beta-sandwich immunoglobulin-like fold whose core is conserved with yeast and human Asf1 but whose surface-charge distribution is distinct [PMID:33501928], and site-directed mutagenesis has identified the specific residues on this surface that mediate H3/H4 binding [PMID:33501928]. Unlike the monomeric yeast and human orthologs, PfAsf1 exists as a dimer in solution through an interface that is variable relative to the conserved histone-interacting surface [PMID:33501928]. Beyond this in vitro chromatin-assembly activity, the broader in vivo pathway context and life-cycle-stage roles of PfAsf1 have not been experimentally characterized in the available corpus.","teleology":[{"year":2009,"claim":"Before any direct biochemistry, it was unknown whether Plasmodium encoded a functional Asf1-type chaperone; data-integration analysis placed PF3D7_1224500 in a conserved histone-loading Hir-Asf1 complex linked to chromatin dynamics during schizogony, framing it as a candidate chromatin-assembly factor.","evidence":"computational sequence profile analysis integrated with high-throughput RNAi, genetic-interaction, and cell-cycle expression datasets","pmids":["19225618"],"confidence":"Low","gaps":["purely computational inference with no direct biochemical experiment on PfAsf1 itself","predicted Hir-Asf1 complex membership and Hpc2p-mediated recruitment not experimentally validated for PfAsf1","proposed schizogony/life-cycle role not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"To establish the structural basis of PfAsf1 function, its N-terminal domain was solved, showing a conserved immunoglobulin-like beta-sandwich fold but a divergent surface-charge distribution, indicating the histone-chaperone architecture is preserved in Plasmodium while surface features have diverged.","evidence":"X-ray crystallography of residues 1–159 at 2.4 Å resolution","pmids":["33501928"],"confidence":"High","gaps":["structure limited to the N-terminal domain; full-length architecture unresolved","no histone-bound co-structure to visualize the interaction directly"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"Whether PfAsf1 shares the monomeric quaternary state of its orthologs was tested; solution cross-linking established that PfAsf1 forms a dimer through an interface distinct from the conserved histone-binding surface, revealing a Plasmodium-specific oligomeric feature.","evidence":"solution cross-linking experiments interpreted alongside the crystal structure","pmids":["33501928"],"confidence":"Medium","gaps":["functional consequence of dimerization for chaperone activity not determined","dimer inferred from cross-linking and crystal packing; not confirmed by orthogonal quantitative methods"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"To demonstrate genuine chaperone activity rather than inferred homology, PfAsf1 was shown to bind Plasmodium H3 and H4 specifically and to deposit H3/H4 dimers onto DNA to form disomes, and the histone-contact residues were pinpointed by mutagenesis, defining the molecular basis of its chromatin-assembly function.","evidence":"in vitro histone deposition (disome formation on a DNA template), binding/pulldown assays, and site-directed mutagenesis of contact residues","pmids":["33501928"],"confidence":"High","gaps":["activity shown in vitro only; in vivo chromatin-assembly role not demonstrated","no test of whether the dimeric state is required for deposition","downstream nucleosome maturation and handoff partners not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The in vivo pathway context of PfAsf1 — its predicted Hir-Asf1 complex membership, stage-specific chromatin functions across the P. falciparum life cycle, and essentiality — remains experimentally unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no direct evidence for PfAsf1 partners or complex membership in vivo","no genetic knockdown/knockout phenotype for PfAsf1 reported","life-cycle-stage-specific roles untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["HISTONE H3","HISTONE H4"],"other_free_text":["N-terminal domain (residues 1–159) adopts an immunoglobulin-like beta-sandwich fold with core conserved to yeast/human Asf1 but divergent surface charge [#0]","Forms a dimer in solution via an interface distinct from the histone-binding surface, unlike monomeric yeast/human Asf1 [#0, #1]","Deposits H3/H4 dimers onto DNA to form disomes in vitro [#2]","Histone-contact residues validated by site-directed mutagenesis [#3]","Computationally predicted membership in a conserved Hir-Asf1 histone-loading complex linked to schizogony (Low-confidence, not experimentally validated) [#4]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"19225618","id":"PMC_19225618","title":"HPC2 and ubinuclein define a novel family of histone chaperones conserved throughout eukaryotes.","date":"2009","source":"Molecular bioSystems","url":"https://pubmed.ncbi.nlm.nih.gov/19225618","citation_count":45,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ASF1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21312235","id":"PMC_21312235","title":"Two nucleus-localized CDK-like kinases with crucial roles for malaria parasite erythrocytic replication are involved in phosphorylation of splicing factor.","date":"2011","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21312235","citation_count":38,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfASF1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33501928","id":"PMC_33501928","title":"Structural insights into histone chaperone Asf1 and its characterization from Plasmodium falciparum.","date":"2021","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/33501928","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ASF1","histone chaperone ASF1","PfASF1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4471,"output_tokens":1248,"usd":0.016067,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6178,"output_tokens":2410,"usd":0.04557,"stage2_stop_reason":"end_turn"},"total_usd":0.061637,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"The N-terminal histone chaperone domain of PfAsf1 (residues 1–159) was solved by X-ray crystallography at 2.4 Å resolution, revealing a beta-sandwich immunoglobulin-like fold with a surface-charge distribution distinct from yeast and human Asf1 despite conserved core structure.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at 2.4 Å with functional validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33501928\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PfAsf1 was found to exist in a dimeric state in solution, distinct from the monomeric forms of yeast and human Asf1, as confirmed by solution cross-linking experiments, and the dimerization interface was shown to be variable relative to the conserved histone-interacting surface.\",\n      \"method\": \"Solution cross-linking experiment\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — crystal structure suggested dimer, confirmed by cross-linking, single lab\",\n      \"pmids\": [\"33501928\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PfAsf1 specifically interacts with Plasmodium histone H3 and H4, and is able to deposit the H3/H4 dimer onto a DNA template to form disomes, demonstrating histone chaperone activity in chromatin assembly.\",\n      \"method\": \"In vitro histone deposition assay (disome formation on DNA template); interaction confirmed by pulldown/binding assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of nucleosome assembly activity with substrate specificity confirmed, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33501928\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Critical residues of PfAsf1 involved in histone H3/H4 interaction were identified and confirmed by site-directed mutagenesis, establishing the molecular basis of its histone-binding activity.\",\n      \"method\": \"Site-directed mutagenesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with functional readout, single lab but rigorous mechanistic approach\",\n      \"pmids\": [\"33501928\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Computational sequence analysis and integration of high-throughput datasets (RNAi knockdowns, genetic and protein interaction maps, cell-cycle gene expression) predicted that PfAsf1 participates in the conserved histone-loading Hir-Asf1 complex and is involved in chromatin dynamics related to schizogony in Plasmodium; the Hpc2p homolog (containing the HUN domain) is proposed to recruit this complex to lineage-specific chromatin reorganization processes.\",\n      \"method\": \"Protein sequence profile analysis; integration of high-throughput RNAi, genetic interaction, and cell-cycle expression datasets\",\n      \"journal\": \"Molecular bioSystems\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational and data-integration inference with no direct biochemical experiment on PfAsf1 itself\",\n      \"pmids\": [\"19225618\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfAsf1 (PF3D7_1224500) is a histone chaperone whose N-terminal domain adopts an immunoglobulin-like beta-sandwich fold and forms a dimer (distinct from yeast/human Asf1); it directly binds Plasmodium histones H3 and H4 through conserved, mutagenesis-validated residues and deposits H3/H4 dimers onto DNA to form disomes, mediating chromatin assembly throughout the P. falciparum life cycle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1224500 (PfAsf1) is a histone chaperone that mediates chromatin assembly in Plasmodium falciparum by binding histones H3 and H4 and depositing H3/H4 dimers onto DNA to form disomes [#2]. Its N-terminal histone chaperone domain (residues 1–159) adopts a beta-sandwich immunoglobulin-like fold whose core is conserved with yeast and human Asf1 but whose surface-charge distribution is distinct [#0], and site-directed mutagenesis has identified the specific residues on this surface that mediate H3/H4 binding [#3]. Unlike the monomeric yeast and human orthologs, PfAsf1 exists as a dimer in solution through an interface that is variable relative to the conserved histone-interacting surface [#0, #1]. Beyond this in vitro chromatin-assembly activity, the broader in vivo pathway context and life-cycle-stage roles of PfAsf1 have not been experimentally characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Before any direct biochemistry, it was unknown whether Plasmodium encoded a functional Asf1-type chaperone; data-integration analysis placed PF3D7_1224500 in a conserved histone-loading Hir-Asf1 complex linked to chromatin dynamics during schizogony, framing it as a candidate chromatin-assembly factor.\",\n      \"evidence\": \"computational sequence profile analysis integrated with high-throughput RNAi, genetic-interaction, and cell-cycle expression datasets\",\n      \"pmids\": [\"19225618\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"purely computational inference with no direct biochemical experiment on PfAsf1 itself\",\n        \"predicted Hir-Asf1 complex membership and Hpc2p-mediated recruitment not experimentally validated for PfAsf1\",\n        \"proposed schizogony/life-cycle role not tested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"To establish the structural basis of PfAsf1 function, its N-terminal domain was solved, showing a conserved immunoglobulin-like beta-sandwich fold but a divergent surface-charge distribution, indicating the histone-chaperone architecture is preserved in Plasmodium while surface features have diverged.\",\n      \"evidence\": \"X-ray crystallography of residues 1–159 at 2.4 Å resolution\",\n      \"pmids\": [\"33501928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"structure limited to the N-terminal domain; full-length architecture unresolved\",\n        \"no histone-bound co-structure to visualize the interaction directly\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether PfAsf1 shares the monomeric quaternary state of its orthologs was tested; solution cross-linking established that PfAsf1 forms a dimer through an interface distinct from the conserved histone-binding surface, revealing a Plasmodium-specific oligomeric feature.\",\n      \"evidence\": \"solution cross-linking experiments interpreted alongside the crystal structure\",\n      \"pmids\": [\"33501928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"functional consequence of dimerization for chaperone activity not determined\",\n        \"dimer inferred from cross-linking and crystal packing; not confirmed by orthogonal quantitative methods\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"To demonstrate genuine chaperone activity rather than inferred homology, PfAsf1 was shown to bind Plasmodium H3 and H4 specifically and to deposit H3/H4 dimers onto DNA to form disomes, and the histone-contact residues were pinpointed by mutagenesis, defining the molecular basis of its chromatin-assembly function.\",\n      \"evidence\": \"in vitro histone deposition (disome formation on a DNA template), binding/pulldown assays, and site-directed mutagenesis of contact residues\",\n      \"pmids\": [\"33501928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"activity shown in vitro only; in vivo chromatin-assembly role not demonstrated\",\n        \"no test of whether the dimeric state is required for deposition\",\n        \"downstream nucleosome maturation and handoff partners not identified\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo pathway context of PfAsf1 — its predicted Hir-Asf1 complex membership, stage-specific chromatin functions across the P. falciparum life cycle, and essentiality — remains experimentally unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"no direct evidence for PfAsf1 partners or complex membership in vivo\",\n        \"no genetic knockdown/knockout phenotype for PfAsf1 reported\",\n        \"life-cycle-stage-specific roles untested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140713\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0042802\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006335\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0006333\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"histone H3\", \"histone H4\"],\n    \"other_free_text\": [\n      \"N-terminal domain (residues 1–159) adopts an immunoglobulin-like beta-sandwich fold with core conserved to yeast/human Asf1 but divergent surface charge [#0]\",\n      \"Forms a dimer in solution via an interface distinct from the histone-binding surface, unlike monomeric yeast/human Asf1 [#0, #1]\",\n      \"Deposits H3/H4 dimers onto DNA to form disomes in vitro [#2]\",\n      \"Histone-contact residues validated by site-directed mutagenesis [#3]\",\n      \"Computationally predicted membership in a conserved Hir-Asf1 histone-loading complex linked to schizogony (Low-confidence, not experimentally validated) [#4]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1224500","name":null,"product":"histone chaperone ASF1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1439400","name":null,"product":"histone chaperone ASF1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1443800","name":null,"product":"histone chaperone ASF1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ASF1","evaluation":null}