{"gene":"PF3D7_1344200","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2019,"finding":"PfGRP170 (PF3D7_1344200) localises to the endoplasmic reticulum of P. falciparum and is essential for asexual growth, being specifically required for proper schizont development, as shown by conditional mutant analysis.","method":"Conditional mutagenesis (inducible knockdown/knockout), fluorescence microscopy for ER localisation","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localisation experiment combined with conditional loss-of-function showing specific schizont-stage growth arrest; published in peer-reviewed journal with multiple orthogonal methods","pmids":["31087747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"GRP170 (PF3D7_1344200) physically interacts with PfBiP (the P. falciparum ER chaperone BiP/Hsp70-2), establishing it as a BiP-interacting ER chaperone.","method":"Co-immunoprecipitation / interaction assay (described in conditional mutant study)","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, single Co-IP method, but consistent with functional role; replicated conceptually in review literature citing the same result","pmids":["31087747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"Loss of GRP170 (PF3D7_1344200) function leads to activation of the P. falciparum eIF2α kinase PK4, placing GRP170 upstream of this parasite stress-response kinase pathway.","method":"Conditional knockdown with downstream pathway readout (PK4 activation assay)","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis placing GRP170 upstream of PK4 established in a single study with conditional mutants, single lab","pmids":["31087747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"GRP170 (PF3D7_1344200) is essential for parasite survival under heat shock, demonstrating a critical role in cellular stress response.","method":"Conditional mutagenesis combined with heat-shock survival assay","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean loss-of-function with defined phenotypic readout (heat-shock sensitivity), single lab, single study","pmids":["31087747"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Recombinant PfGRP170 (PF3D7_1344200) exhibits basal ATPase activity and can suppress heat-induced aggregation of the model substrate malate dehydrogenase in a nucleotide-independent manner, demonstrating independent chaperone (holdase) function.","method":"In vitro ATPase assay and heat-induced aggregation suppression assay with recombinant protein expressed in E. coli","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical reconstitution with two orthogonal functional assays (ATPase and holdase), single lab","pmids":["40730633"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"ATP binding perturbs the structural stability of PfGRP170 (PF3D7_1344200), making it more sensitive to heat stress and proteolytic cleavage, as shown by secondary structure analysis and proteolysis assays in the presence and absence of nucleotides.","method":"Circular dichroism / secondary structure analysis, proteolytic cleavage assays, molecular docking and molecular dynamics simulations","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1–3 / Moderate — in vitro biochemical and biophysical experiments with recombinant protein (structure modulation), supplemented by computational simulations; single lab","pmids":["40730633"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"GRP170 (PF3D7_1344200) was co-precipitated with PfRh5 in a pull-down experiment from P. falciparum parasites, indicating a physical association. However, inducible knockout of GRP170 did not affect PMX processing of PfRh5, showing that GRP170 function is not required for this specific step. The GRP170-iKO arrested at the late schizont stage in the first cycle, consistent with its essential role in schizont development.","method":"Pull-down/co-immunoprecipitation from parasite lysate; inducible knockout with growth and processing assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down identifying physical association, combined with conditional KO and functional readout (PfRh5 processing and parasite growth), single study","pmids":["37072430"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfGRP170 (PF3D7_1344200) is an ER-resident chaperone in P. falciparum that physically interacts with BiP (PfHsp70-2), exhibits basal ATPase activity and nucleotide-independent holdase function (suppression of substrate aggregation), is essential for schizont-stage asexual development and for surviving heat shock, and acts upstream of the eIF2α kinase PK4 in the parasite stress-response pathway; its structural stability is modulated by ATP binding."},"narrative":{"mechanistic_narrative":"GRP170 (PF3D7_1344200) is an endoplasmic reticulum-resident chaperone of Plasmodium falciparum that is essential for asexual blood-stage development, being specifically required for proper schizont maturation [PMID:31087747]. It functions as a partner of the ER Hsp70 chaperone BiP (PfHsp70-2), with which it physically associates [PMID:31087747], and as an independent chaperone it exhibits basal ATPase activity and suppresses heat-induced aggregation of a model substrate in a nucleotide-independent holdase mode [PMID:40730633]; ATP binding itself destabilizes the protein, rendering it more susceptible to heat stress and proteolysis [PMID:40730633]. GRP170 is critical for parasite survival under heat shock and acts upstream of the eIF2α kinase PK4 in the stress-response pathway, since loss of GRP170 function triggers PK4 activation [PMID:31087747]. GRP170 also co-precipitates with the invasion ligand PfRh5, although its loss does not impair PMX-mediated processing of PfRh5, indicating this association is not required for that step [PMID:37072430].","teleology":[{"year":2019,"claim":"Establishing where GRP170 acts and whether it matters answered the basic question of its cellular role: it is an ER-resident, essential chaperone with a stage-specific requirement.","evidence":"Conditional mutagenesis with inducible loss-of-function and fluorescence microscopy in P. falciparum","pmids":["31087747"],"confidence":"High","gaps":["Molecular basis of the schizont-stage specificity not defined","Substrate repertoire in the ER not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"Identifying a binding partner placed GRP170 within the ER chaperone machinery by showing it physically associates with BiP/Hsp70-2.","evidence":"Co-immunoprecipitation from parasite lysate","pmids":["31087747"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Whether GRP170 acts as a nucleotide-exchange factor for BiP not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"Linking GRP170 loss to PK4 activation and heat-shock lethality connected the chaperone to the parasite stress-response pathway and placed it genetically upstream of the eIF2α kinase.","evidence":"Conditional knockdown with PK4 activation readout and heat-shock survival assay in P. falciparum","pmids":["31087747"],"confidence":"Medium","gaps":["Mechanism by which GRP170 loss activates PK4 not resolved","Direct versus indirect epistasis with PK4 not distinguished"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Testing a physical association with the invasion ligand PfRh5 clarified the functional boundaries of GRP170, showing it associates with PfRh5 but is dispensable for PfRh5 processing.","evidence":"Pull-down from parasite lysate plus inducible knockout with growth and PMX-processing assays in P. falciparum","pmids":["37072430"],"confidence":"Medium","gaps":["Functional consequence of the PfRh5 association unknown","Whether the interaction is direct or complex-mediated not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Biochemical reconstitution answered whether GRP170 has intrinsic chaperone activity, demonstrating basal ATPase activity and nucleotide-independent holdase function, and revealing that ATP binding destabilizes the protein.","evidence":"In vitro ATPase and aggregation-suppression assays, circular dichroism, proteolysis assays, and molecular dynamics with recombinant E. coli-expressed protein","pmids":["40730633"],"confidence":"High","gaps":["Physiological substrates in vivo not identified","Relationship between ATP-induced destabilization and holdase cycle not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How GRP170 cooperates with BiP mechanistically and what its endogenous ER client proteins are remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No native substrate identified","Molecular mechanism coupling GRP170 to PK4-mediated stress signaling not established","Structural model of GRP170-BiP cooperation absent"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFBIP / PFHSP70-2 (PF3D7_0917900)","PK4 (EIF2Α KINASE)","PFRH5"],"other_free_text":["Essential for asexual blood-stage growth, with loss of function causing arrest at the late schizont stage [#0, #6].","Intrinsic holdase activity is nucleotide-independent, whereas ATP binding destabilizes the protein and increases its heat and protease sensitivity [#4, #5].","Co-precipitates with PfRh5 but is not required for PMX-mediated PfRh5 processing [#6]."]}},"prefetch_data":{},"corpus_meta":[{"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":["PfGRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40730633","id":"PMC_40730633","title":"Biochemical and biophysical characterization of Plasmodium falciparum glucose regulated protein 170.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40730633","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170","PfGRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39670568","id":"","title":"Characterization and Inhibition of the Chaperone Function of Plasmodium falciparum Glucose-Regulated Protein 94 kDa (Pf Grp94).","date":"2024","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/39670568","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38518861","id":"","title":"Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update.","date":"2024","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/38518861","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37072430","id":"","title":"Plasmepsin X activates the PCRCR complex of Plasmodium falciparum by processing PfRh5 for erythrocyte invasion.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37072430","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37702516","id":"","title":"Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses.","date":"2023","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/37702516","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35652103","id":"","title":"Plasmodium falciparum Molecular Chaperones: Guardians of the Malaria Parasite Proteome and Renovators of the Host Proteome.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35652103","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35992276","id":"","title":"HSP70 and their co-chaperones in the human malaria parasite P. falciparum and their potential as drug targets.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/35992276","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31280465","id":"","title":"Comparative structure-function features of Hsp70s of Plasmodium falciparum and human origins.","date":"2019","source":"Biophysical reviews","url":"https://pubmed.ncbi.nlm.nih.gov/31280465","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35637187","id":"","title":"Stochastic expression of invasion genes in Plasmodium falciparum schizonts.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35637187","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32388921","id":"","title":"Directing traffic: Chaperone-mediated protein transport in malaria parasites.","date":"2020","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32388921","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31775392","id":"","title":"Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31775392","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GRP170"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13668,"output_tokens":1760,"usd":0.033702,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6870,"output_tokens":2331,"usd":0.046312,"stage2_stop_reason":"end_turn"},"total_usd":0.080014,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"PfGRP170 (PF3D7_1344200) localises to the endoplasmic reticulum of P. falciparum and is essential for asexual growth, being specifically required for proper schizont development, as shown by conditional mutant analysis.\",\n      \"method\": \"Conditional mutagenesis (inducible knockdown/knockout), fluorescence microscopy for ER localisation\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localisation experiment combined with conditional loss-of-function showing specific schizont-stage growth arrest; published in peer-reviewed journal with multiple orthogonal methods\",\n      \"pmids\": [\"31087747\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GRP170 (PF3D7_1344200) physically interacts with PfBiP (the P. falciparum ER chaperone BiP/Hsp70-2), establishing it as a BiP-interacting ER chaperone.\",\n      \"method\": \"Co-immunoprecipitation / interaction assay (described in conditional mutant study)\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, single Co-IP method, but consistent with functional role; replicated conceptually in review literature citing the same result\",\n      \"pmids\": [\"31087747\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of GRP170 (PF3D7_1344200) function leads to activation of the P. falciparum eIF2α kinase PK4, placing GRP170 upstream of this parasite stress-response kinase pathway.\",\n      \"method\": \"Conditional knockdown with downstream pathway readout (PK4 activation assay)\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis placing GRP170 upstream of PK4 established in a single study with conditional mutants, single lab\",\n      \"pmids\": [\"31087747\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GRP170 (PF3D7_1344200) is essential for parasite survival under heat shock, demonstrating a critical role in cellular stress response.\",\n      \"method\": \"Conditional mutagenesis combined with heat-shock survival assay\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean loss-of-function with defined phenotypic readout (heat-shock sensitivity), single lab, single study\",\n      \"pmids\": [\"31087747\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Recombinant PfGRP170 (PF3D7_1344200) exhibits basal ATPase activity and can suppress heat-induced aggregation of the model substrate malate dehydrogenase in a nucleotide-independent manner, demonstrating independent chaperone (holdase) function.\",\n      \"method\": \"In vitro ATPase assay and heat-induced aggregation suppression assay with recombinant protein expressed in E. coli\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical reconstitution with two orthogonal functional assays (ATPase and holdase), single lab\",\n      \"pmids\": [\"40730633\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATP binding perturbs the structural stability of PfGRP170 (PF3D7_1344200), making it more sensitive to heat stress and proteolytic cleavage, as shown by secondary structure analysis and proteolysis assays in the presence and absence of nucleotides.\",\n      \"method\": \"Circular dichroism / secondary structure analysis, proteolytic cleavage assays, molecular docking and molecular dynamics simulations\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–3 / Moderate — in vitro biochemical and biophysical experiments with recombinant protein (structure modulation), supplemented by computational simulations; single lab\",\n      \"pmids\": [\"40730633\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GRP170 (PF3D7_1344200) was co-precipitated with PfRh5 in a pull-down experiment from P. falciparum parasites, indicating a physical association. However, inducible knockout of GRP170 did not affect PMX processing of PfRh5, showing that GRP170 function is not required for this specific step. The GRP170-iKO arrested at the late schizont stage in the first cycle, consistent with its essential role in schizont development.\",\n      \"method\": \"Pull-down/co-immunoprecipitation from parasite lysate; inducible knockout with growth and processing assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down identifying physical association, combined with conditional KO and functional readout (PfRh5 processing and parasite growth), single study\",\n      \"pmids\": [\"37072430\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfGRP170 (PF3D7_1344200) is an ER-resident chaperone in P. falciparum that physically interacts with BiP (PfHsp70-2), exhibits basal ATPase activity and nucleotide-independent holdase function (suppression of substrate aggregation), is essential for schizont-stage asexual development and for surviving heat shock, and acts upstream of the eIF2α kinase PK4 in the parasite stress-response pathway; its structural stability is modulated by ATP binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GRP170 (PF3D7_1344200) is an endoplasmic reticulum-resident chaperone of Plasmodium falciparum that is essential for asexual blood-stage development, being specifically required for proper schizont maturation [#0]. It functions as a partner of the ER Hsp70 chaperone BiP (PfHsp70-2), with which it physically associates [#1], and as an independent chaperone it exhibits basal ATPase activity and suppresses heat-induced aggregation of a model substrate in a nucleotide-independent holdase mode [#4]; ATP binding itself destabilizes the protein, rendering it more susceptible to heat stress and proteolysis [#5]. GRP170 is critical for parasite survival under heat shock and acts upstream of the eIF2\\u03b1 kinase PK4 in the stress-response pathway, since loss of GRP170 function triggers PK4 activation [#2, #3]. GRP170 also co-precipitates with the invasion ligand PfRh5, although its loss does not impair PMX-mediated processing of PfRh5, indicating this association is not required for that step [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing where GRP170 acts and whether it matters answered the basic question of its cellular role: it is an ER-resident, essential chaperone with a stage-specific requirement.\",\n      \"evidence\": \"Conditional mutagenesis with inducible loss-of-function and fluorescence microscopy in P. falciparum\",\n      \"pmids\": [\"31087747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the schizont-stage specificity not defined\", \"Substrate repertoire in the ER not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying a binding partner placed GRP170 within the ER chaperone machinery by showing it physically associates with BiP/Hsp70-2.\",\n      \"evidence\": \"Co-immunoprecipitation from parasite lysate\",\n      \"pmids\": [\"31087747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Whether GRP170 acts as a nucleotide-exchange factor for BiP not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking GRP170 loss to PK4 activation and heat-shock lethality connected the chaperone to the parasite stress-response pathway and placed it genetically upstream of the eIF2\\u03b1 kinase.\",\n      \"evidence\": \"Conditional knockdown with PK4 activation readout and heat-shock survival assay in P. falciparum\",\n      \"pmids\": [\"31087747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which GRP170 loss activates PK4 not resolved\", \"Direct versus indirect epistasis with PK4 not distinguished\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Testing a physical association with the invasion ligand PfRh5 clarified the functional boundaries of GRP170, showing it associates with PfRh5 but is dispensable for PfRh5 processing.\",\n      \"evidence\": \"Pull-down from parasite lysate plus inducible knockout with growth and PMX-processing assays in P. falciparum\",\n      \"pmids\": [\"37072430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the PfRh5 association unknown\", \"Whether the interaction is direct or complex-mediated not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Biochemical reconstitution answered whether GRP170 has intrinsic chaperone activity, demonstrating basal ATPase activity and nucleotide-independent holdase function, and revealing that ATP binding destabilizes the protein.\",\n      \"evidence\": \"In vitro ATPase and aggregation-suppression assays, circular dichroism, proteolysis assays, and molecular dynamics with recombinant E. coli-expressed protein\",\n      \"pmids\": [\"40730633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates in vivo not identified\", \"Relationship between ATP-induced destabilization and holdase cycle not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GRP170 cooperates with BiP mechanistically and what its endogenous ER client proteins are remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No native substrate identified\", \"Molecular mechanism coupling GRP170 to PK4-mediated stress signaling not established\", \"Structural model of GRP170-BiP cooperation absent\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005524\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0051087\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005788\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006986\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0034976\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PfBiP / PfHsp70-2 (PF3D7_0917900)\", \"PK4 (eIF2\\u03b1 kinase)\", \"PfRh5\"],\n    \"other_free_text\": [\n      \"Essential for asexual blood-stage growth, with loss of function causing arrest at the late schizont stage [#0, #6].\",\n      \"Intrinsic holdase activity is nucleotide-independent, whereas ATP binding destabilizes the protein and increases its heat and protease sensitivity [#4, #5].\",\n      \"Co-precipitates with PfRh5 but is not required for PMX-mediated PfRh5 processing [#6].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1344200","name":null,"product":"endoplasmic reticulum chaperone GRP170","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1357200","name":null,"product":"endoplasmic reticulum chaperone GRP170, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1257200","name":null,"product":"endoplasmic reticulum chaperone GRP170, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"GRP170","evaluation":null}