{"gene":"PF3D7_0907700","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2019,"finding":"Crystal structure of PfPA28 (PF3D7_0907700) reveals a bell-shaped heptameric molecule with an inner pore displaying strong charge segregation; disordered loops not resolved in the crystal structure extend from the heptamer and surround the pore, as shown by small-angle X-ray scattering.","method":"X-ray crystallography and small-angle X-ray scattering (SAXS)","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with SAXS, both orthogonal structural methods in a single rigorous study","pmids":["31384003"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"PfPA28 (PF3D7_0907700) forms a complex with the Pf20S proteasome core, capping one or both ends; cryo-EM structures at 3.9 Å (singly capped) and 3.8 Å (doubly capped) show that PfPA28 binds Pf20S asymmetrically, strongly engaging subunits on only one side of the core.","method":"Single-particle cryo-electron microscopy","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution cryo-EM structures of the complex, two capping states resolved in a single rigorous study","pmids":["31384003"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"PfPA28 (PF3D7_0907700) undergoes rigid body motions relative to Pf20S and molecular dynamics simulations support conformational flexibility and a leaky interface between PfPA28 and Pf20S, suggesting lateral transfer of short peptides through the dynamic interface as a mechanism for releasing proteasome degradation products.","method":"Molecular dynamics simulation informed by cryo-EM structure","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 1 structure / Weak — MD simulation-based mechanistic proposal derived from structural data in a single study; not experimentally validated independently","pmids":["31384003"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"Genetic deletion (knockout) of PfPA28 (PF3D7_0907700) renders P. falciparum parasites more sensitive to dihydroartemisinin, indicating that PA28 plays a role in protection against proteotoxic stress in vivo.","method":"Genetic knockout with drug sensitivity assay (dihydroartemisinin IC50)","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with defined phenotypic readout (DHA hypersensitivity), single lab but combined with structural work in the same study","pmids":["31384003"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"PfPA28 (PF3D7_0907700) stimulates Pf20S proteasome peptidase activity in vitro in a ubiquitin- and ATP-independent manner.","method":"In vitro peptidase activity assay with purified PfPA28 and Pf20S","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution; finding also independently referenced in PMID:39497850 and PMID:34155201","pmids":["31384003"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"By complexome profiling of P. falciparum asexual blood-stage lysates, PA28 (PF3D7_0907700) was found exclusively co-migrating with the larger 20S proteasome assembly and not with the 19S regulatory particle assemblies, placing it specifically within the 20S-associated complex rather than the 26S/30S proteasome.","method":"Complexome profiling (native PAGE separation combined with mass spectrometry)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complexome profiling provides direct biochemical evidence of complex membership, single lab study","pmids":["34155201"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfPA28 (PF3D7_0907700) forms a bell-shaped heptameric cap that binds asymmetrically to the Pf20S proteasome core (exclusively within the 20S assembly, not the 26S), stimulates its peptidase activity in a ubiquitin- and ATP-independent manner via a conformationally flexible and leaky interface proposed to facilitate lateral egress of degradation products, and protects P. falciparum against proteotoxic stress in vivo, as demonstrated by hypersensitivity to dihydroartemisinin upon its genetic deletion."},"narrative":{"mechanistic_narrative":"PF3D7_0907700 (PA28) is a proteasome activator that protects Plasmodium falciparum against proteotoxic stress by stimulating proteasomal peptide degradation [PMID:31384003]. It assembles into a bell-shaped heptamer whose inner pore shows strong charge segregation, with disordered loops extending from the heptamer to surround the pore [PMID:31384003]. This heptamer caps one or both ends of the Pf20S proteasome core, engaging the core asymmetrically to form singly and doubly capped complexes [PMID:31384003], and it associates specifically with the 20S assembly rather than the 19S regulatory particle or the 26S/30S proteasome [PMID:34155201]. Functionally, PF3D7_0907700 stimulates Pf20S peptidase activity in a ubiquitin- and ATP-independent manner [PMID:31384003], and molecular dynamics based on the cryo-EM structure indicates a conformationally flexible, leaky PA28–Pf20S interface that could permit lateral egress of short degradation products [PMID:31384003]. Genetic deletion of PF3D7_0907700 sensitizes parasites to dihydroartemisinin, linking this activity to defense against proteotoxic stress in vivo [PMID:31384003].","teleology":[{"year":2019,"claim":"The architecture of PF3D7_0907700 was unknown; solving its structure established that it forms a bell-shaped heptameric activator with a charge-segregated pore flanked by disordered loops.","evidence":"X-ray crystallography combined with SAXS on purified PfPA28","pmids":["31384003"],"confidence":"High","gaps":["Function of the disordered loops surrounding the pore not resolved structurally","Stoichiometry of subunit assembly in vivo not directly addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"How PF3D7_0907700 engages the proteasome was unknown; cryo-EM of the PA28–Pf20S complex showed it caps one or both ends of the 20S core and binds asymmetrically, defining the mode of proteasome engagement.","evidence":"Single-particle cryo-EM of singly (3.9 Å) and doubly (3.8 Å) capped complexes","pmids":["31384003"],"confidence":"High","gaps":["Structural basis of asymmetric engagement not mechanistically explained","Regulation of singly vs doubly capped states in vivo unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"The functional consequence of PA28 binding was untested; in vitro reconstitution showed PF3D7_0907700 stimulates Pf20S peptidase activity without ubiquitin or ATP, establishing it as a bona fide proteasome activator.","evidence":"In vitro peptidase activity assay with purified PfPA28 and Pf20S","pmids":["31384003"],"confidence":"High","gaps":["Physiological substrates degraded via PA28-Pf20S not identified","Whether activation is substrate-selective not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"The mechanism of product release was unknown; MD simulations from the cryo-EM structure proposed a flexible, leaky interface allowing lateral egress of short peptides.","evidence":"Molecular dynamics simulation informed by cryo-EM structure","pmids":["31384003"],"confidence":"Medium","gaps":["Simulation-based proposal not experimentally validated independently","Direct demonstration of lateral peptide transfer lacking"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"The biological role of PA28 was unknown; genetic knockout sensitized parasites to dihydroartemisinin, linking PF3D7_0907700 to defense against proteotoxic stress in vivo.","evidence":"Genetic knockout with dihydroartemisinin IC50 drug sensitivity assay","pmids":["31384003"],"confidence":"High","gaps":["Molecular pathway connecting PA28 loss to DHA hypersensitivity not defined","Role across developmental stages beyond the assayed condition unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"It was unclear whether PA28 associates with the 19S/26S machinery; complexome profiling placed PF3D7_0907700 exclusively with the 20S assembly, confirming it is a dedicated 20S cap rather than a 26S component.","evidence":"Complexome profiling (native PAGE with mass spectrometry) of asexual blood-stage lysates","pmids":["34155201"],"confidence":"Medium","gaps":["Whether PA28 and 19S can co-occupy the same 20S core (hybrid particles) not addressed","Stage- or condition-dependent complex composition not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The endogenous substrate repertoire and the signals governing PA28 recruitment to Pf20S under proteotoxic stress remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No physiological substrates identified","Regulatory triggers for PA28-Pf20S assembly unknown","Lateral egress mechanism awaits experimental validation"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PA28-capped Pf20S proteasome (singly and doubly capped)","20S proteasome assembly"],"partners":["PF20S PROTEASOME CORE"],"other_free_text":["Forms a bell-shaped heptamer with a charge-segregated inner pore and disordered pore-surrounding loops [#0]","Caps Pf20S asymmetrically, strongly engaging subunits on only one side of the core [#1]","Associates exclusively with the 20S assembly, not the 19S regulatory particle or 26S/30S proteasome [#5]","Stimulates peptidase activity independently of ubiquitin and ATP [#4]","Conformationally flexible, leaky PA28-Pf20S interface proposed to permit lateral egress of degradation products (MD-based) [#2]","Knockout confers dihydroartemisinin hypersensitivity, implicating a role in protection against proteotoxic stress [#3]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"31384003","id":"PMC_31384003","title":"The structure of the PA28-20S proteasome complex from Plasmodium falciparum and implications for proteostasis.","date":"2019","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31384003","citation_count":37,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28","PfPA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39497850","id":"","title":"Ubiquitin-proteasome system in Plasmodium: a potential antimalarial target to overcome resistance - a systematic review.","date":"2024","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39497850","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39436072","id":"","title":"Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance in Plasmodium falciparum.","date":"2024","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/39436072","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39084225","id":"","title":"Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.","date":"2024","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/39084225","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37067430","id":"","title":"Chemogenomic Profiling of a Plasmodium falciparum Transposon Mutant Library Reveals Shared Effects of Dihydroartemisinin and Bortezomib on Lipid Metabolism and Exported Proteins.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/37067430","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34188457","id":"","title":"Prediction of Human-Plasmodium vivax Protein Associations From Heterogeneous Network Structures Based on Machine-Learning Approach.","date":"2021","source":"Bioinformatics and biology insights","url":"https://pubmed.ncbi.nlm.nih.gov/34188457","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41301442","id":"","title":"Cleaving Expectations: A Review of Proteasome Functional and Catalytic Diversity.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41301442","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33648890","id":"","title":"MalDA, Accelerating Malaria Drug Discovery.","date":"2021","source":"Trends in parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/33648890","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34155201","id":"","title":"Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum.","date":"2021","source":"Nature 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32033280","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28852696","id":"","title":"The Proteasome in Modern Drug Discovery: Second Life of a Highly Valuable Drug Target.","date":"2017","source":"ACS central science","url":"https://pubmed.ncbi.nlm.nih.gov/28852696","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25943340","id":"","title":"Evolution of proteasome regulators in eukaryotes.","date":"2015","source":"Genome biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/25943340","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26090380","id":"","title":"Role of the Ubiquitin-Proteasome Systems in the Biology and Virulence of Protozoan Parasites.","date":"2015","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/26090380","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PA28"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16826,"output_tokens":1529,"usd":0.036707,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6526,"output_tokens":2656,"usd":0.049515,"stage2_stop_reason":"end_turn"},"total_usd":0.086222,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of PfPA28 (PF3D7_0907700) reveals a bell-shaped heptameric molecule with an inner pore displaying strong charge segregation; disordered loops not resolved in the crystal structure extend from the heptamer and surround the pore, as shown by small-angle X-ray scattering.\",\n      \"method\": \"X-ray crystallography and small-angle X-ray scattering (SAXS)\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with SAXS, both orthogonal structural methods in a single rigorous study\",\n      \"pmids\": [\"31384003\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PfPA28 (PF3D7_0907700) forms a complex with the Pf20S proteasome core, capping one or both ends; cryo-EM structures at 3.9 Å (singly capped) and 3.8 Å (doubly capped) show that PfPA28 binds Pf20S asymmetrically, strongly engaging subunits on only one side of the core.\",\n      \"method\": \"Single-particle cryo-electron microscopy\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution cryo-EM structures of the complex, two capping states resolved in a single rigorous study\",\n      \"pmids\": [\"31384003\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PfPA28 (PF3D7_0907700) undergoes rigid body motions relative to Pf20S and molecular dynamics simulations support conformational flexibility and a leaky interface between PfPA28 and Pf20S, suggesting lateral transfer of short peptides through the dynamic interface as a mechanism for releasing proteasome degradation products.\",\n      \"method\": \"Molecular dynamics simulation informed by cryo-EM structure\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 structure / Weak — MD simulation-based mechanistic proposal derived from structural data in a single study; not experimentally validated independently\",\n      \"pmids\": [\"31384003\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genetic deletion (knockout) of PfPA28 (PF3D7_0907700) renders P. falciparum parasites more sensitive to dihydroartemisinin, indicating that PA28 plays a role in protection against proteotoxic stress in vivo.\",\n      \"method\": \"Genetic knockout with drug sensitivity assay (dihydroartemisinin IC50)\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with defined phenotypic readout (DHA hypersensitivity), single lab but combined with structural work in the same study\",\n      \"pmids\": [\"31384003\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PfPA28 (PF3D7_0907700) stimulates Pf20S proteasome peptidase activity in vitro in a ubiquitin- and ATP-independent manner.\",\n      \"method\": \"In vitro peptidase activity assay with purified PfPA28 and Pf20S\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution; finding also independently referenced in PMID:39497850 and PMID:34155201\",\n      \"pmids\": [\"31384003\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"By complexome profiling of P. falciparum asexual blood-stage lysates, PA28 (PF3D7_0907700) was found exclusively co-migrating with the larger 20S proteasome assembly and not with the 19S regulatory particle assemblies, placing it specifically within the 20S-associated complex rather than the 26S/30S proteasome.\",\n      \"method\": \"Complexome profiling (native PAGE separation combined with mass spectrometry)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complexome profiling provides direct biochemical evidence of complex membership, single lab study\",\n      \"pmids\": [\"34155201\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfPA28 (PF3D7_0907700) forms a bell-shaped heptameric cap that binds asymmetrically to the Pf20S proteasome core (exclusively within the 20S assembly, not the 26S), stimulates its peptidase activity in a ubiquitin- and ATP-independent manner via a conformationally flexible and leaky interface proposed to facilitate lateral egress of degradation products, and protects P. falciparum against proteotoxic stress in vivo, as demonstrated by hypersensitivity to dihydroartemisinin upon its genetic deletion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0907700 (PA28) is a proteasome activator that protects Plasmodium falciparum against proteotoxic stress by stimulating proteasomal peptide degradation [#3, #4]. It assembles into a bell-shaped heptamer whose inner pore shows strong charge segregation, with disordered loops extending from the heptamer to surround the pore [#0]. This heptamer caps one or both ends of the Pf20S proteasome core, engaging the core asymmetrically to form singly and doubly capped complexes [#1], and it associates specifically with the 20S assembly rather than the 19S regulatory particle or the 26S/30S proteasome [#5]. Functionally, PF3D7_0907700 stimulates Pf20S peptidase activity in a ubiquitin- and ATP-independent manner [#4], and molecular dynamics based on the cryo-EM structure indicates a conformationally flexible, leaky PA28–Pf20S interface that could permit lateral egress of short degradation products [#2]. Genetic deletion of PF3D7_0907700 sensitizes parasites to dihydroartemisinin, linking this activity to defense against proteotoxic stress in vivo [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"The architecture of PF3D7_0907700 was unknown; solving its structure established that it forms a bell-shaped heptameric activator with a charge-segregated pore flanked by disordered loops.\",\n      \"evidence\": \"X-ray crystallography combined with SAXS on purified PfPA28\",\n      \"pmids\": [\"31384003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the disordered loops surrounding the pore not resolved structurally\", \"Stoichiometry of subunit assembly in vivo not directly addressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How PF3D7_0907700 engages the proteasome was unknown; cryo-EM of the PA28–Pf20S complex showed it caps one or both ends of the 20S core and binds asymmetrically, defining the mode of proteasome engagement.\",\n      \"evidence\": \"Single-particle cryo-EM of singly (3.9 Å) and doubly (3.8 Å) capped complexes\",\n      \"pmids\": [\"31384003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of asymmetric engagement not mechanistically explained\", \"Regulation of singly vs doubly capped states in vivo unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The functional consequence of PA28 binding was untested; in vitro reconstitution showed PF3D7_0907700 stimulates Pf20S peptidase activity without ubiquitin or ATP, establishing it as a bona fide proteasome activator.\",\n      \"evidence\": \"In vitro peptidase activity assay with purified PfPA28 and Pf20S\",\n      \"pmids\": [\"31384003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates degraded via PA28-Pf20S not identified\", \"Whether activation is substrate-selective not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The mechanism of product release was unknown; MD simulations from the cryo-EM structure proposed a flexible, leaky interface allowing lateral egress of short peptides.\",\n      \"evidence\": \"Molecular dynamics simulation informed by cryo-EM structure\",\n      \"pmids\": [\"31384003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Simulation-based proposal not experimentally validated independently\", \"Direct demonstration of lateral peptide transfer lacking\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The biological role of PA28 was unknown; genetic knockout sensitized parasites to dihydroartemisinin, linking PF3D7_0907700 to defense against proteotoxic stress in vivo.\",\n      \"evidence\": \"Genetic knockout with dihydroartemisinin IC50 drug sensitivity assay\",\n      \"pmids\": [\"31384003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway connecting PA28 loss to DHA hypersensitivity not defined\", \"Role across developmental stages beyond the assayed condition unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"It was unclear whether PA28 associates with the 19S/26S machinery; complexome profiling placed PF3D7_0907700 exclusively with the 20S assembly, confirming it is a dedicated 20S cap rather than a 26S component.\",\n      \"evidence\": \"Complexome profiling (native PAGE with mass spectrometry) of asexual blood-stage lysates\",\n      \"pmids\": [\"34155201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PA28 and 19S can co-occupy the same 20S core (hybrid particles) not addressed\", \"Stage- or condition-dependent complex composition not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous substrate repertoire and the signals governing PA28 recruitment to Pf20S under proteotoxic stress remain undefined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No physiological substrates identified\", \"Regulatory triggers for PA28-Pf20S assembly unknown\", \"Lateral egress mechanism awaits experimental validation\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0061133\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0008537\", \"supporting_discovery_ids\": [4, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0043161\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0006515\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"PA28-capped Pf20S proteasome (singly and doubly capped)\",\n      \"20S proteasome assembly\"\n    ],\n    \"partners\": [\n      \"Pf20S proteasome core\"\n    ],\n    \"other_free_text\": [\n      \"Forms a bell-shaped heptamer with a charge-segregated inner pore and disordered pore-surrounding loops [#0]\",\n      \"Caps Pf20S asymmetrically, strongly engaging subunits on only one side of the core [#1]\",\n      \"Associates exclusively with the 20S assembly, not the 19S regulatory particle or 26S/30S proteasome [#5]\",\n      \"Stimulates peptidase activity independently of ubiquitin and ATP [#4]\",\n      \"Conformationally flexible, leaky PA28-Pf20S interface proposed to permit lateral egress of degradation products (MD-based) [#2]\",\n      \"Knockout confers dihydroartemisinin hypersensitivity, implicating a role in protection against proteotoxic stress [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0907700","name":null,"product":"proteasome activator 28","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0809100","name":null,"product":"proteasome activator 28, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0705500","name":null,"product":"proteasome activator 28, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PA28","evaluation":null}