{"gene":"PF3D7_0628200","run_date":"2026-09-08T12:51:26","timeline":{"discoveries":[{"year":1997,"finding":"PK4 (PF3D7_0628200) was cloned and characterized as a eukaryotic initiation factor-2α (eIF-2α) kinase-related protein kinase from P. falciparum. The recombinant protein expressed in E. coli phosphorylates a synthetic peptide representing an eIF-2α kinase substrate, and both autophosphorylation and substrate phosphorylation are inhibited by haemin. The protein is expressed as 80 and 90 kDa forms; the 80 kDa form is present throughout intraerythrocytic development and in merozoites, while the 90 kDa forms appear only in mature parasites. Confocal microscopy showed diffuse distribution in trophozoites and punctate foci in segmenters, with co-localization with apical membrane antigen-1 (AMA-1) at the apical complex in segmenters and merozoites.","method":"Molecular cloning, recombinant protein expression in E. coli, in vitro kinase assay (peptide phosphorylation), Western blot, confocal microscopy, subcellular fractionation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with recombinant protein plus multiple orthogonal methods (Western blot, confocal microscopy, fractionation) in a single focused study","pmids":["9371731"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"PK4 phosphorylates the regulatory serine 59 of Plasmodium eIF2α and this activity is essential for completion of the erythrocytic cycle. PK4 activity leads to arrest of global protein synthesis in schizonts (where daughter merozoites develop) and in gametocytes. Genetic disruption of PK4 demonstrated its essentiality for erythrocytic schizogony.","method":"Reverse genetics (gene disruption/conditional knockdown), phosphorylation site identification (Ser59 of eIF2α), global protein synthesis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetics with defined cellular phenotype (arrest of protein synthesis in schizonts/gametocytes) and identified phosphorylation substrate site, single lab but multiple orthogonal methods","pmids":["22355110"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"ART treatment induces phosphorylation of parasite eIF2α mediated specifically by PK4. This phosphorylation represses global translation and triggers latency (dormancy). Overexpression of a dominant-negative PK4 or pharmacological inhibition of PK4 blocked parasites from entering ART-induced latency and abolished recrudescence after ART treatment in infected mice, placing PK4 as the central kinase mediating ART-induced translational repression and latency.","method":"Dominant-negative overexpression, pharmacological inhibition of PK4, phospho-eIF2α Western blot, mouse infection model measuring recrudescence, translation assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic (dominant-negative) and pharmacological inhibition approaches with in vivo recrudescence readout and mechanistic phosphorylation data, multiple orthogonal methods in one study","pmids":["29241041"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"Loss of the ER chaperone PfGRP170 function leads to activation of PK4, placing PK4 downstream of ER stress/unfolded protein response signaling in P. falciparum. This was shown by conditional knockdown of PfGRP170 followed by measurement of PK4 activation (phospho-eIF2α readout).","method":"Conditional knockdown of PfGRP170, phospho-eIF2α readout as proxy for PK4 activation, epistasis","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, indirect activation readout (phospho-eIF2α) without direct PK4 biochemistry; establishes pathway placement but not direct PK4 mechanism","pmids":["31087747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"A kinome-wide reverse genetics screen identified PK4 as one of 36 parasite kinases likely essential for erythrocytic schizogony in P. falciparum.","method":"Kinome-wide reverse genetics (attempted gene disruption), phospho-proteomic analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — large-scale screen with genetic disruption attempts, single method per gene, no specific mechanistic follow-up for PK4 individually","pmids":["22127061"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PK4 (PF3D7_0628200) is a P. falciparum eIF2α kinase that phosphorylates Ser59 of parasite eIF2α to repress global protein synthesis during schizogony and gametocytogenesis; it is essential for the erythrocytic cycle, is activated downstream of ER stress/unfolded protein response (via PfGRP170), and mediates artemisinin-induced translational repression and parasite latency, with its inhibition blocking recrudescence after artemisinin treatment."},"narrative":{"mechanistic_narrative":"PK4 (PF3D7_0628200) is a Plasmodium falciparum eukaryotic initiation factor-2α (eIF-2α) kinase that controls the translational state of the parasite by phosphorylating the regulatory Ser59 of parasite eIF2α, thereby arresting global protein synthesis during the erythrocytic cycle [PMID:9371731, PMID:22355110]. The recombinant kinase autophosphorylates and phosphorylates an eIF-2α substrate peptide, activities inhibited by haemin, and it is expressed as 80 and 90 kDa forms across intraerythrocytic development with apical-complex localization co-localizing with AMA-1 in segmenters and merozoites [PMID:9371731]. Genetic disruption established that PK4 activity is essential for completion of erythrocytic schizogony, with eIF2α phosphorylation repressing translation in schizonts and gametocytes [PMID:22355110, PMID:22127061]. PK4 is activated downstream of ER stress: conditional loss of the ER chaperone PfGRP170 triggers PK4 activation, linking it to the unfolded protein response [PMID:31087747]. PK4 is also the central kinase mediating artemisinin (ART)-induced eIF2α phosphorylation, translational repression, and parasite latency, since dominant-negative PK4 or pharmacological inhibition blocks entry into ART-induced dormancy and abolishes recrudescence in infected mice [PMID:29241041].","teleology":[{"year":1997,"claim":"Before its molecular identity was known, it was unclear whether P. falciparum possessed a dedicated eIF-2α kinase; cloning and biochemical characterization established PK4 as a functional eIF-2α kinase-related protein kinase with a regulated expression and localization pattern.","evidence":"Molecular cloning, recombinant expression in E. coli, in vitro peptide kinase assay, Western blot, and confocal microscopy in P. falciparum","pmids":["9371731"],"confidence":"High","gaps":["Physiological substrate not confirmed in parasite at this stage","Functional consequence of the 80 vs 90 kDa forms not resolved","Significance of apical AMA-1 co-localization for kinase function unknown"],"attribution":[]},{"year":2011,"claim":"It was unknown which parasite kinases are indispensable for blood-stage growth; a kinome-wide disruption screen placed PK4 among kinases likely essential for erythrocytic schizogony.","evidence":"Kinome-wide reverse genetics disruption attempts with phospho-proteomic analysis in P. falciparum","pmids":["22127061"],"confidence":"Medium","gaps":["Screen provides essentiality inference, not a defined PK4 mechanism","No PK4-specific follow-up in this study"],"attribution":[]},{"year":2012,"claim":"The in vivo substrate and cellular role were undefined; targeted genetics showed PK4 phosphorylates eIF2α at Ser59 to arrest global protein synthesis in schizonts and gametocytes, and that this activity is required for the erythrocytic cycle.","evidence":"Reverse genetics disruption/knockdown, Ser59 phosphorylation site identification, and global protein synthesis assays in P. falciparum","pmids":["22355110"],"confidence":"High","gaps":["Upstream activating signals not defined here","How translational arrest is coordinated with schizogony/gametocytogenesis not resolved"],"attribution":[]},{"year":2017,"claim":"The kinase responsible for artemisinin-induced dormancy was unknown; reciprocal dominant-negative and pharmacological inhibition identified PK4 as the central kinase mediating ART-induced eIF2α phosphorylation, translational repression, latency, and recrudescence.","evidence":"Dominant-negative overexpression, pharmacological PK4 inhibition, phospho-eIF2α Western blot, and mouse recrudescence model in P. falciparum","pmids":["29241041"],"confidence":"High","gaps":["Molecular sensor coupling ART to PK4 activation not defined","Structural basis of PK4 inhibition by the pharmacological agent not established"],"attribution":[]},{"year":2019,"claim":"The signals activating PK4 were unclear; epistasis via PfGRP170 knockdown placed PK4 downstream of ER stress/unfolded protein response signaling.","evidence":"Conditional knockdown of PfGRP170 with phospho-eIF2α readout as proxy for PK4 activation in P. falciparum","pmids":["31087747"],"confidence":"Medium","gaps":["Activation inferred from phospho-eIF2α proxy rather than direct PK4 biochemistry","Direct physical/mechanistic link between PfGRP170 and PK4 not shown","Whether ER stress activation and ART activation converge on the same mechanism unresolved"],"attribution":[]},{"year":null,"claim":"The direct molecular mechanism of PK4 activation and the structural basis for its regulation remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PK4 in the corpus","Direct upstream activators binding PK4 not identified","Whether the haemin sensitivity observed in vitro reflects physiological regulation is uncharacterized"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["EIF2Α (PARASITE SUBSTRATE, PHOSPHORYLATED AT SER59) [#1]","PFGRP170 (ER CHAPERONE UPSTREAM OF PK4 ACTIVATION) [#3]","AMA-1 (APICAL-COMPLEX CO-LOCALIZATION IN SEGMENTERS/MEROZOITES) [#0]"],"other_free_text":["Recombinant PK4 autophosphorylation and substrate phosphorylation are inhibited by haemin in vitro [#0]","Expressed as 80 kDa (throughout development and in merozoites) and 90 kDa (mature parasites only) forms [#0]","Essential for erythrocytic schizogony; loss-of-function genetics [#1, #4]","Central mediator of artemisinin-induced translational repression, latency, and recrudescence; inhibition blocks dormancy in a mouse model [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"22127061","id":"PMC_22127061","title":"Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum.","date":"2011","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/22127061","citation_count":288,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29241041","id":"PMC_29241041","title":"Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency.","date":"2017","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/29241041","citation_count":105,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22355110","id":"PMC_22355110","title":"PK4, a eukaryotic initiation factor 2α(eIF2α) kinase, is essential for the development of the erythrocytic cycle of Plasmodium.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22355110","citation_count":80,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26955948","id":"PMC_26955948","title":"Plasmodium falciparum: multifaceted resistance to artemisinins.","date":"2016","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/26955948","citation_count":79,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfPK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9371731","id":"PMC_9371731","title":"Molecular cloning, characterization and localization of PfPK4, an eIF-2alpha kinase-related enzyme from the malarial parasite Plasmodium falciparum.","date":"1997","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9371731","citation_count":47,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfPK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31087747","id":"PMC_31087747","title":"The endoplasmic reticulum chaperone PfGRP170 is essential for asexual development and is linked to stress response in malaria parasites.","date":"2019","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31087747","citation_count":23,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22421875","id":"PMC_22421875","title":"Parasite physiology: Plasmodium gets the PK4 blood test.","date":"2012","source":"Nature reviews. Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22421875","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40396048","id":"PMC_40396048","title":"The ART of Resistance.","date":"2022","source":"Autophagy reports","url":"https://pubmed.ncbi.nlm.nih.gov/40396048","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29241036","id":"PMC_29241036","title":"Plasmodium Peekaboo: PK4 Mediates Parasite Latency.","date":"2017","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/29241036","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41120634","id":"PMC_41120634","title":"Computational insights into harmala alkaloids as novel antimalarial candidates against Plasmodium falciparum.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41120634","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PK4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6869,"output_tokens":1644,"usd":0.022634,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6732,"output_tokens":2640,"usd":0.04983,"stage2_stop_reason":"end_turn"},"total_usd":0.072464,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"PK4 (PF3D7_0628200) was cloned and characterized as a eukaryotic initiation factor-2α (eIF-2α) kinase-related protein kinase from P. falciparum. The recombinant protein expressed in E. coli phosphorylates a synthetic peptide representing an eIF-2α kinase substrate, and both autophosphorylation and substrate phosphorylation are inhibited by haemin. The protein is expressed as 80 and 90 kDa forms; the 80 kDa form is present throughout intraerythrocytic development and in merozoites, while the 90 kDa forms appear only in mature parasites. Confocal microscopy showed diffuse distribution in trophozoites and punctate foci in segmenters, with co-localization with apical membrane antigen-1 (AMA-1) at the apical complex in segmenters and merozoites.\",\n      \"method\": \"Molecular cloning, recombinant protein expression in E. coli, in vitro kinase assay (peptide phosphorylation), Western blot, confocal microscopy, subcellular fractionation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with recombinant protein plus multiple orthogonal methods (Western blot, confocal microscopy, fractionation) in a single focused study\",\n      \"pmids\": [\"9371731\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PK4 phosphorylates the regulatory serine 59 of Plasmodium eIF2α and this activity is essential for completion of the erythrocytic cycle. PK4 activity leads to arrest of global protein synthesis in schizonts (where daughter merozoites develop) and in gametocytes. Genetic disruption of PK4 demonstrated its essentiality for erythrocytic schizogony.\",\n      \"method\": \"Reverse genetics (gene disruption/conditional knockdown), phosphorylation site identification (Ser59 of eIF2α), global protein synthesis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetics with defined cellular phenotype (arrest of protein synthesis in schizonts/gametocytes) and identified phosphorylation substrate site, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22355110\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ART treatment induces phosphorylation of parasite eIF2α mediated specifically by PK4. This phosphorylation represses global translation and triggers latency (dormancy). Overexpression of a dominant-negative PK4 or pharmacological inhibition of PK4 blocked parasites from entering ART-induced latency and abolished recrudescence after ART treatment in infected mice, placing PK4 as the central kinase mediating ART-induced translational repression and latency.\",\n      \"method\": \"Dominant-negative overexpression, pharmacological inhibition of PK4, phospho-eIF2α Western blot, mouse infection model measuring recrudescence, translation assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic (dominant-negative) and pharmacological inhibition approaches with in vivo recrudescence readout and mechanistic phosphorylation data, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29241041\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of the ER chaperone PfGRP170 function leads to activation of PK4, placing PK4 downstream of ER stress/unfolded protein response signaling in P. falciparum. This was shown by conditional knockdown of PfGRP170 followed by measurement of PK4 activation (phospho-eIF2α readout).\",\n      \"method\": \"Conditional knockdown of PfGRP170, phospho-eIF2α readout as proxy for PK4 activation, epistasis\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect activation readout (phospho-eIF2α) without direct PK4 biochemistry; establishes pathway placement but not direct PK4 mechanism\",\n      \"pmids\": [\"31087747\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A kinome-wide reverse genetics screen identified PK4 as one of 36 parasite kinases likely essential for erythrocytic schizogony in P. falciparum.\",\n      \"method\": \"Kinome-wide reverse genetics (attempted gene disruption), phospho-proteomic analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — large-scale screen with genetic disruption attempts, single method per gene, no specific mechanistic follow-up for PK4 individually\",\n      \"pmids\": [\"22127061\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PK4 (PF3D7_0628200) is a P. falciparum eIF2α kinase that phosphorylates Ser59 of parasite eIF2α to repress global protein synthesis during schizogony and gametocytogenesis; it is essential for the erythrocytic cycle, is activated downstream of ER stress/unfolded protein response (via PfGRP170), and mediates artemisinin-induced translational repression and parasite latency, with its inhibition blocking recrudescence after artemisinin treatment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PK4 (PF3D7_0628200) is a Plasmodium falciparum eukaryotic initiation factor-2\\u03b1 (eIF-2\\u03b1) kinase that controls the translational state of the parasite by phosphorylating the regulatory Ser59 of parasite eIF2\\u03b1, thereby arresting global protein synthesis during the erythrocytic cycle [#0, #1]. The recombinant kinase autophosphorylates and phosphorylates an eIF-2\\u03b1 substrate peptide, activities inhibited by haemin, and it is expressed as 80 and 90 kDa forms across intraerythrocytic development with apical-complex localization co-localizing with AMA-1 in segmenters and merozoites [#0]. Genetic disruption established that PK4 activity is essential for completion of erythrocytic schizogony, with eIF2\\u03b1 phosphorylation repressing translation in schizonts and gametocytes [#1, #4]. PK4 is activated downstream of ER stress: conditional loss of the ER chaperone PfGRP170 triggers PK4 activation, linking it to the unfolded protein response [#3]. PK4 is also the central kinase mediating artemisinin (ART)-induced eIF2\\u03b1 phosphorylation, translational repression, and parasite latency, since dominant-negative PK4 or pharmacological inhibition blocks entry into ART-induced dormancy and abolishes recrudescence in infected mice [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Before its molecular identity was known, it was unclear whether P. falciparum possessed a dedicated eIF-2\\u03b1 kinase; cloning and biochemical characterization established PK4 as a functional eIF-2\\u03b1 kinase-related protein kinase with a regulated expression and localization pattern.\",\n      \"evidence\": \"Molecular cloning, recombinant expression in E. coli, in vitro peptide kinase assay, Western blot, and confocal microscopy in P. falciparum\",\n      \"pmids\": [\"9371731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate not confirmed in parasite at this stage\", \"Functional consequence of the 80 vs 90 kDa forms not resolved\", \"Significance of apical AMA-1 co-localization for kinase function unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"It was unknown which parasite kinases are indispensable for blood-stage growth; a kinome-wide disruption screen placed PK4 among kinases likely essential for erythrocytic schizogony.\",\n      \"evidence\": \"Kinome-wide reverse genetics disruption attempts with phospho-proteomic analysis in P. falciparum\",\n      \"pmids\": [\"22127061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Screen provides essentiality inference, not a defined PK4 mechanism\", \"No PK4-specific follow-up in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The in vivo substrate and cellular role were undefined; targeted genetics showed PK4 phosphorylates eIF2\\u03b1 at Ser59 to arrest global protein synthesis in schizonts and gametocytes, and that this activity is required for the erythrocytic cycle.\",\n      \"evidence\": \"Reverse genetics disruption/knockdown, Ser59 phosphorylation site identification, and global protein synthesis assays in P. falciparum\",\n      \"pmids\": [\"22355110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activating signals not defined here\", \"How translational arrest is coordinated with schizogony/gametocytogenesis not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The kinase responsible for artemisinin-induced dormancy was unknown; reciprocal dominant-negative and pharmacological inhibition identified PK4 as the central kinase mediating ART-induced eIF2\\u03b1 phosphorylation, translational repression, latency, and recrudescence.\",\n      \"evidence\": \"Dominant-negative overexpression, pharmacological PK4 inhibition, phospho-eIF2\\u03b1 Western blot, and mouse recrudescence model in P. falciparum\",\n      \"pmids\": [\"29241041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor coupling ART to PK4 activation not defined\", \"Structural basis of PK4 inhibition by the pharmacological agent not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The signals activating PK4 were unclear; epistasis via PfGRP170 knockdown placed PK4 downstream of ER stress/unfolded protein response signaling.\",\n      \"evidence\": \"Conditional knockdown of PfGRP170 with phospho-eIF2\\u03b1 readout as proxy for PK4 activation in P. falciparum\",\n      \"pmids\": [\"31087747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Activation inferred from phospho-eIF2\\u03b1 proxy rather than direct PK4 biochemistry\", \"Direct physical/mechanistic link between PfGRP170 and PK4 not shown\", \"Whether ER stress activation and ART activation converge on the same mechanism unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular mechanism of PK4 activation and the structural basis for its regulation remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PK4 in the corpus\", \"Direct upstream activators binding PK4 not identified\", \"Whether the haemin sensitivity observed in vitro reflects physiological regulation is uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004694\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0004672\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0046777\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031982\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0017148\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0030968\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0034976\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"eIF2\\u03b1 (parasite substrate, phosphorylated at Ser59) [#1]\",\n      \"PfGRP170 (ER chaperone upstream of PK4 activation) [#3]\",\n      \"AMA-1 (apical-complex co-localization in segmenters/merozoites) [#0]\"\n    ],\n    \"other_free_text\": [\n      \"Recombinant PK4 autophosphorylation and substrate phosphorylation are inhibited by haemin in vitro [#0]\",\n      \"Expressed as 80 kDa (throughout development and in merozoites) and 90 kDa (mature parasites only) forms [#0]\",\n      \"Essential for erythrocytic schizogony; loss-of-function genetics [#1, #4]\",\n      \"Central mediator of artemisinin-induced translational repression, latency, and recrudescence; inhibition blocks dormancy in a mouse model [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0628200","name":null,"product":"eukaryotic translation initiation factor 2-alpha kinase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1126900","name":null,"product":"eukaryotic translation initiation factor 2-alpha kinase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1121600","name":null,"product":"eukaryotic translation initiation factor 2-alpha kinase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PK4","evaluation":null}