{"gene":"PF3D7_1361000","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2013,"finding":"PF3D7_1361000 (PRMT5) associates with PfSmD1, a core spliceosomal Sm protein, as shown by pull-down assays and co-immunoprecipitation, and co-localizes with PfSmD1 by immunofluorescence, indicating PRMT5 is part of a methylosome-like complex involved in cytoplasmic assembly of Sm proteins.","method":"Pull-down assay, co-immunoprecipitation, immunofluorescence co-localization, MALDI-TOF spectrometry","journal":"Malaria journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and pull-down with MALDI-TOF identification in a single lab, two complementary methods (biochemical interaction + localization)","pmids":["24047207"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"The interaction of PfSMN (survival of motor neuron, tudor domain-containing protein) with PfSmD1 is methylation-dependent, consistent with PRMT5 methylating arginine residues on SmD1 to enable this interaction.","method":"Yeast two-hybrid analysis, in vitro pull-down assays","journal":"Malaria journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (yeast two-hybrid + pull-down) in a single lab establish methylation-dependent interaction","pmids":["24047207"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"PF3D7_1361000 (PRMT5) catalyzes symmetric dimethylation of histone H3 at R2 (H3R2me2s) and R8, and histone H4 at R3, as demonstrated by in vitro methyltransferase assay with purified protein.","method":"In vitro methyltransferase assay with purified recombinant PfPRMT5","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with purified protein, multiple histone substrates identified in a single rigorous study","pmids":["37349497"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"Disruption of PF3D7_1361000 (PRMT5) causes asexual stage growth defects primarily through reduced merozoite invasion efficiency, accompanied by downregulation of invasion-related transcripts and depletion of the active chromatin mark H3R2me2s at invasion-related genes.","method":"Genetic disruption (conditional knockout/disruptant line), transcriptomic analysis, genome-wide chromatin profiling (ChIP-seq)","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined invasion phenotype corroborated by transcriptomics and genome-wide chromatin profiling in a single rigorous study","pmids":["37349497"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"PF3D7_1361000 (PRMT5) associates with invasion-related transcriptional regulators AP2-I, BDP1, and GCN5, as identified by interactome studies.","method":"Interactome/co-immunoprecipitation coupled with mass spectrometry","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single interactome study from one lab; binding partners identified but not reciprocally validated","pmids":["37349497"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"Disruption of PF3D7_1361000 (PRMT5) causes substantial anomalies in RNA splicing events, including those for invasion-related genes, establishing a functional role for PRMT5 in RNA splicing regulation in P. falciparum.","method":"Genetic disruption (disruptant parasite line), transcriptomic/splicing analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic disruption with defined splicing phenotype from a single lab study","pmids":["37349497"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Onametostat inhibits the in vitro methyltransferase activity of purified PF3D7_1361000 (PRMT5), and a shift in onametostat IC50 was observed in a PRMT5-disruptant parasite line, confirming PRMT5 as the primary target of onametostat in P. falciparum.","method":"In vitro methyltransferase inhibition assay with purified PfPRMT5, IC50 shift assay in disruptant parasite line","journal":"Antimicrobial agents and chemotherapy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical inhibition of purified enzyme confirmed by genetic target validation (IC50 shift in disruptant line), two orthogonal methods","pmids":["39194263"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Onametostat treatment reduces H3R2me2s levels in P. falciparum and causes defects in merozoite invasion of red blood cells, functionally linking PRMT5 catalytic activity (H3R2me2s) to invasion gene regulation.","method":"Pharmacological inhibition with onametostat, western blot for H3R2me2s, invasion assay","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with mechanistic chromatin mark readout and phenotypic invasion assay, corroborating findings from genetic disruption study","pmids":["39194263"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1361000 (PRMT5) is a type II protein arginine methyltransferase in P. falciparum that catalyzes symmetric dimethylation of histone H3R2, H3R8, and H4R3 (H3R2me2s being an active chromatin mark), associates with spliceosomal Sm proteins (including SmD1) and transcriptional regulators (AP2-I, BDP1, GCN5) as part of a methylosome-like complex, and is required for proper RNA splicing and merozoite invasion of red blood cells, with its loss causing depletion of H3R2me2s at invasion-related genes, downregulation of invasion transcripts, and reduced invasion efficiency."},"narrative":{"mechanistic_narrative":"PF3D7_1361000 (PRMT5) is a type II protein arginine methyltransferase in Plasmodium falciparum that couples histone arginine methylation to the regulation of red blood cell invasion [PMID:37349497]. Purified recombinant PRMT5 catalyzes symmetric dimethylation of histone H3 at R2 (H3R2me2s) and R8 and of histone H4 at R3 in vitro [PMID:37349497]. It operates within a methylosome-like complex, associating with the core spliceosomal Sm protein PfSmD1 and co-localizing with it, consistent with a role in cytoplasmic Sm-protein assembly [PMID:24047207], and it further associates with the invasion-related transcriptional regulators AP2-I, BDP1, and GCN5 [PMID:37349497]. Functionally, disruption of PRMT5 impairs asexual growth chiefly through reduced merozoite invasion efficiency, with depletion of the active mark H3R2me2s at invasion genes, downregulation of invasion transcripts, and widespread RNA splicing anomalies including at invasion-related genes [PMID:37349497]. Pharmacological inhibition with onametostat, whose primary target PRMT5 has been genetically confirmed, reduces H3R2me2s and phenocopies the invasion defect, linking PRMT5 catalytic activity to invasion gene expression [PMID:39194263].","teleology":[{"year":2013,"claim":"Establishing PRMT5's physical context: whether it participates in a methylosome-like assembly was unknown, and demonstrating its association with the spliceosomal Sm protein PfSmD1 placed it in a complex governing Sm-protein assembly.","evidence":"Pull-down, co-immunoprecipitation, immunofluorescence co-localization and MALDI-TOF in P. falciparum","pmids":["24047207"],"confidence":"Medium","gaps":["Direct methylation of SmD1 by PRMT5 was inferred, not demonstrated enzymatically","Stoichiometry and full composition of the methylosome-like complex not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Whether arginine methylation is functionally required for downstream Sm-protein interactions was open; the methylation-dependent PfSMN–PfSmD1 interaction argued that PRMT5-type methylation licenses these contacts.","evidence":"Yeast two-hybrid and in vitro pull-down assays in P. falciparum","pmids":["24047207"],"confidence":"Medium","gaps":["PRMT5 itself was not shown to be the methyltransferase responsible for the SmD1 mark in this assay","In vivo relevance of the methylation-dependent interaction not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"The enzymatic identity of PRMT5 was defined by showing purified protein catalyzes symmetric dimethylation of specific histone arginines, establishing it as a type II arginine methyltransferase acting on chromatin.","evidence":"In vitro methyltransferase assay with purified recombinant PfPRMT5","pmids":["37349497"],"confidence":"High","gaps":["Relative in vivo contribution of each histone substrate (H3R2, H3R8, H4R3) not resolved","Non-histone substrates beyond SmD1-type proteins not systematically mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"The biological consequence of PRMT5 loss was unknown; genetic disruption tied it to merozoite invasion via loss of H3R2me2s and downregulation of invasion transcripts, defining its role in the asexual cycle.","evidence":"Genetic disruption, transcriptomics, and genome-wide ChIP-seq in P. falciparum","pmids":["37349497"],"confidence":"High","gaps":["Direct chain of causality from mark loss to specific invasion-gene silencing not dissected gene-by-gene","Whether transcriptional and splicing defects act independently or jointly on invasion unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Whether PRMT5 acts on RNA processing in addition to chromatin was addressed by showing its disruption causes RNA splicing anomalies, connecting its Sm-protein association to a functional splicing role.","evidence":"Genetic disruption with transcriptomic/splicing analysis in P. falciparum","pmids":["37349497"],"confidence":"Medium","gaps":["Mechanistic link between PRMT5 methyltransferase activity and specific splicing events not established","Splicing defects not separated from chromatin-driven effects on invasion phenotype"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"To connect PRMT5 to invasion regulation at the complex level, interactome analysis identified associations with the transcriptional regulators AP2-I, BDP1, and GCN5.","evidence":"Interactome/co-IP coupled with mass spectrometry in P. falciparum","pmids":["37349497"],"confidence":"Medium","gaps":["Single interactome study without reciprocal validation of the partners","Whether these associations are direct or bridged by other factors unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Whether PRMT5 is a druggable and validated target was tested; onametostat inhibited purified enzyme and showed an IC50 shift in a disruptant line, confirming PRMT5 as its primary target in P. falciparum.","evidence":"In vitro methyltransferase inhibition and IC50-shift assay in a PRMT5-disruptant parasite line","pmids":["39194263"],"confidence":"High","gaps":["Selectivity of onametostat against other parasite methyltransferases not quantified","In vivo efficacy not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"To close the loop between catalytic activity and phenotype, pharmacological inhibition was shown to reduce H3R2me2s and impair invasion, phenocopying genetic disruption.","evidence":"Onametostat treatment with western blot for H3R2me2s and invasion assay in P. falciparum","pmids":["39194263"],"confidence":"Medium","gaps":["Temporal ordering of mark loss versus invasion-gene shutdown not resolved","Off-target contributions to the invasion phenotype not fully excluded"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How PRMT5's chromatin (H3R2me2s) and splicing functions are mechanistically integrated to control invasion, and which non-histone substrates it methylates in vivo, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PRMT5 or its complexes","Direct in vivo substrate map beyond histones undefined","Mechanism coupling arginine methylation to specific splicing outcomes unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["methylosome-like complex (with PfSmD1)","PRMT5 association with AP2-I / BDP1 / GCN5"],"partners":["PFSMD1","AP2-I","BDP1","GCN5"],"other_free_text":["Catalyzes symmetric dimethylation of histone H3R2 (H3R2me2s, an active chromatin mark), H3R8, and H4R3 [#2]","Loss depletes H3R2me2s at invasion genes and downregulates invasion transcripts, reducing merozoite invasion efficiency [#3]","Onametostat is a confirmed catalytic inhibitor whose primary target is PRMT5 [#6, #7]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"24047207","id":"PMC_24047207","title":"Organization of Plasmodium falciparum spliceosomal core complex and role of arginine methylation in its assembly.","date":"2013","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/24047207","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfPRMT5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37349497","id":"PMC_37349497","title":"A type II protein arginine methyltransferase regulates merozoite invasion in Plasmodium falciparum.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37349497","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfPRMT5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39194263","id":"PMC_39194263","title":"Onametostat, a PfPRMT5 inhibitor, exhibits antimalarial activity to Plasmodium falciparum.","date":"2024","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/39194263","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfPRMT5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4519,"output_tokens":2077,"usd":0.022356,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7280,"output_tokens":3503,"usd":0.061988,"stage2_stop_reason":"end_turn"},"total_usd":0.084344,"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\": 2013,\n      \"finding\": \"PF3D7_1361000 (PRMT5) associates with PfSmD1, a core spliceosomal Sm protein, as shown by pull-down assays and co-immunoprecipitation, and co-localizes with PfSmD1 by immunofluorescence, indicating PRMT5 is part of a methylosome-like complex involved in cytoplasmic assembly of Sm proteins.\",\n      \"method\": \"Pull-down assay, co-immunoprecipitation, immunofluorescence co-localization, MALDI-TOF spectrometry\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and pull-down with MALDI-TOF identification in a single lab, two complementary methods (biochemical interaction + localization)\",\n      \"pmids\": [\"24047207\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The interaction of PfSMN (survival of motor neuron, tudor domain-containing protein) with PfSmD1 is methylation-dependent, consistent with PRMT5 methylating arginine residues on SmD1 to enable this interaction.\",\n      \"method\": \"Yeast two-hybrid analysis, in vitro pull-down assays\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (yeast two-hybrid + pull-down) in a single lab establish methylation-dependent interaction\",\n      \"pmids\": [\"24047207\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PF3D7_1361000 (PRMT5) catalyzes symmetric dimethylation of histone H3 at R2 (H3R2me2s) and R8, and histone H4 at R3, as demonstrated by in vitro methyltransferase assay with purified protein.\",\n      \"method\": \"In vitro methyltransferase assay with purified recombinant PfPRMT5\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with purified protein, multiple histone substrates identified in a single rigorous study\",\n      \"pmids\": [\"37349497\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Disruption of PF3D7_1361000 (PRMT5) causes asexual stage growth defects primarily through reduced merozoite invasion efficiency, accompanied by downregulation of invasion-related transcripts and depletion of the active chromatin mark H3R2me2s at invasion-related genes.\",\n      \"method\": \"Genetic disruption (conditional knockout/disruptant line), transcriptomic analysis, genome-wide chromatin profiling (ChIP-seq)\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined invasion phenotype corroborated by transcriptomics and genome-wide chromatin profiling in a single rigorous study\",\n      \"pmids\": [\"37349497\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PF3D7_1361000 (PRMT5) associates with invasion-related transcriptional regulators AP2-I, BDP1, and GCN5, as identified by interactome studies.\",\n      \"method\": \"Interactome/co-immunoprecipitation coupled with mass spectrometry\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single interactome study from one lab; binding partners identified but not reciprocally validated\",\n      \"pmids\": [\"37349497\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Disruption of PF3D7_1361000 (PRMT5) causes substantial anomalies in RNA splicing events, including those for invasion-related genes, establishing a functional role for PRMT5 in RNA splicing regulation in P. falciparum.\",\n      \"method\": \"Genetic disruption (disruptant parasite line), transcriptomic/splicing analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic disruption with defined splicing phenotype from a single lab study\",\n      \"pmids\": [\"37349497\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Onametostat inhibits the in vitro methyltransferase activity of purified PF3D7_1361000 (PRMT5), and a shift in onametostat IC50 was observed in a PRMT5-disruptant parasite line, confirming PRMT5 as the primary target of onametostat in P. falciparum.\",\n      \"method\": \"In vitro methyltransferase inhibition assay with purified PfPRMT5, IC50 shift assay in disruptant parasite line\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical inhibition of purified enzyme confirmed by genetic target validation (IC50 shift in disruptant line), two orthogonal methods\",\n      \"pmids\": [\"39194263\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Onametostat treatment reduces H3R2me2s levels in P. falciparum and causes defects in merozoite invasion of red blood cells, functionally linking PRMT5 catalytic activity (H3R2me2s) to invasion gene regulation.\",\n      \"method\": \"Pharmacological inhibition with onametostat, western blot for H3R2me2s, invasion assay\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with mechanistic chromatin mark readout and phenotypic invasion assay, corroborating findings from genetic disruption study\",\n      \"pmids\": [\"39194263\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1361000 (PRMT5) is a type II protein arginine methyltransferase in P. falciparum that catalyzes symmetric dimethylation of histone H3R2, H3R8, and H4R3 (H3R2me2s being an active chromatin mark), associates with spliceosomal Sm proteins (including SmD1) and transcriptional regulators (AP2-I, BDP1, GCN5) as part of a methylosome-like complex, and is required for proper RNA splicing and merozoite invasion of red blood cells, with its loss causing depletion of H3R2me2s at invasion-related genes, downregulation of invasion transcripts, and reduced invasion efficiency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1361000 (PRMT5) is a type II protein arginine methyltransferase in Plasmodium falciparum that couples histone arginine methylation to the regulation of red blood cell invasion [#2, #3]. Purified recombinant PRMT5 catalyzes symmetric dimethylation of histone H3 at R2 (H3R2me2s) and R8 and of histone H4 at R3 in vitro [#2]. It operates within a methylosome-like complex, associating with the core spliceosomal Sm protein PfSmD1 and co-localizing with it, consistent with a role in cytoplasmic Sm-protein assembly [#0], and it further associates with the invasion-related transcriptional regulators AP2-I, BDP1, and GCN5 [#4]. Functionally, disruption of PRMT5 impairs asexual growth chiefly through reduced merozoite invasion efficiency, with depletion of the active mark H3R2me2s at invasion genes, downregulation of invasion transcripts, and widespread RNA splicing anomalies including at invasion-related genes [#3, #5]. Pharmacological inhibition with onametostat, whose primary target PRMT5 has been genetically confirmed, reduces H3R2me2s and phenocopies the invasion defect, linking PRMT5 catalytic activity to invasion gene expression [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing PRMT5's physical context: whether it participates in a methylosome-like assembly was unknown, and demonstrating its association with the spliceosomal Sm protein PfSmD1 placed it in a complex governing Sm-protein assembly.\",\n      \"evidence\": \"Pull-down, co-immunoprecipitation, immunofluorescence co-localization and MALDI-TOF in P. falciparum\",\n      \"pmids\": [\"24047207\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direct methylation of SmD1 by PRMT5 was inferred, not demonstrated enzymatically\",\n        \"Stoichiometry and full composition of the methylosome-like complex not defined\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether arginine methylation is functionally required for downstream Sm-protein interactions was open; the methylation-dependent PfSMN–PfSmD1 interaction argued that PRMT5-type methylation licenses these contacts.\",\n      \"evidence\": \"Yeast two-hybrid and in vitro pull-down assays in P. falciparum\",\n      \"pmids\": [\"24047207\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"PRMT5 itself was not shown to be the methyltransferase responsible for the SmD1 mark in this assay\",\n        \"In vivo relevance of the methylation-dependent interaction not tested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The enzymatic identity of PRMT5 was defined by showing purified protein catalyzes symmetric dimethylation of specific histone arginines, establishing it as a type II arginine methyltransferase acting on chromatin.\",\n      \"evidence\": \"In vitro methyltransferase assay with purified recombinant PfPRMT5\",\n      \"pmids\": [\"37349497\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Relative in vivo contribution of each histone substrate (H3R2, H3R8, H4R3) not resolved\",\n        \"Non-histone substrates beyond SmD1-type proteins not systematically mapped\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The biological consequence of PRMT5 loss was unknown; genetic disruption tied it to merozoite invasion via loss of H3R2me2s and downregulation of invasion transcripts, defining its role in the asexual cycle.\",\n      \"evidence\": \"Genetic disruption, transcriptomics, and genome-wide ChIP-seq in P. falciparum\",\n      \"pmids\": [\"37349497\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direct chain of causality from mark loss to specific invasion-gene silencing not dissected gene-by-gene\",\n        \"Whether transcriptional and splicing defects act independently or jointly on invasion unresolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether PRMT5 acts on RNA processing in addition to chromatin was addressed by showing its disruption causes RNA splicing anomalies, connecting its Sm-protein association to a functional splicing role.\",\n      \"evidence\": \"Genetic disruption with transcriptomic/splicing analysis in P. falciparum\",\n      \"pmids\": [\"37349497\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Mechanistic link between PRMT5 methyltransferase activity and specific splicing events not established\",\n        \"Splicing defects not separated from chromatin-driven effects on invasion phenotype\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To connect PRMT5 to invasion regulation at the complex level, interactome analysis identified associations with the transcriptional regulators AP2-I, BDP1, and GCN5.\",\n      \"evidence\": \"Interactome/co-IP coupled with mass spectrometry in P. falciparum\",\n      \"pmids\": [\"37349497\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single interactome study without reciprocal validation of the partners\",\n        \"Whether these associations are direct or bridged by other factors unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether PRMT5 is a druggable and validated target was tested; onametostat inhibited purified enzyme and showed an IC50 shift in a disruptant line, confirming PRMT5 as its primary target in P. falciparum.\",\n      \"evidence\": \"In vitro methyltransferase inhibition and IC50-shift assay in a PRMT5-disruptant parasite line\",\n      \"pmids\": [\"39194263\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Selectivity of onametostat against other parasite methyltransferases not quantified\",\n        \"In vivo efficacy not addressed\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To close the loop between catalytic activity and phenotype, pharmacological inhibition was shown to reduce H3R2me2s and impair invasion, phenocopying genetic disruption.\",\n      \"evidence\": \"Onametostat treatment with western blot for H3R2me2s and invasion assay in P. falciparum\",\n      \"pmids\": [\"39194263\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Temporal ordering of mark loss versus invasion-gene shutdown not resolved\",\n        \"Off-target contributions to the invasion phenotype not fully excluded\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRMT5's chromatin (H3R2me2s) and splicing functions are mechanistically integrated to control invasion, and which non-histone substrates it methylates in vivo, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structural model of PRMT5 or its complexes\",\n        \"Direct in vivo substrate map beyond histones undefined\",\n        \"Mechanism coupling arginine methylation to specific splicing outcomes unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0035242\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0035243\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008380\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0006355\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\n      \"methylosome-like complex (with PfSmD1)\",\n      \"PRMT5 association with AP2-I / BDP1 / GCN5\"\n    ],\n    \"partners\": [\n      \"PfSmD1\",\n      \"AP2-I\",\n      \"BDP1\",\n      \"GCN5\"\n    ],\n    \"other_free_text\": [\n      \"Catalyzes symmetric dimethylation of histone H3R2 (H3R2me2s, an active chromatin mark), H3R8, and H4R3 [#2]\",\n      \"Loss depletes H3R2me2s at invasion genes and downregulates invasion transcripts, reducing merozoite invasion efficiency [#3]\",\n      \"Onametostat is a confirmed catalytic inhibitor whose primary target is PRMT5 [#6, #7]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1361000","name":null,"product":"protein arginine N-methyltransferase 5, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1137100","name":null,"product":"protein arginine N-methyltransferase 5, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1110400","name":null,"product":"protein arginine N-methyltransferase 5, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PRMT5","evaluation":null}