{"gene":"PF3D7_1136700","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2019,"finding":"PfAIP (PF3D7_1136700) localizes to the rhoptries in P. falciparum, and conditional mislocalization of PfAIP leads to deficient red blood cell invasion, establishing an essential role in host cell invasion.","method":"Conditional mislocalization system (DiCre-based), fluorescence microscopy","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional mislocalization with defined invasion phenotype, single lab, two orthogonal methods (localization + functional assay)","pmids":["31877322"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"PfARO armadillo repeat mutations identified by structural guidance cause mislocalization of PfAIP, indicating that PfAIP rhoptry targeting depends on direct interaction with PfARO.","method":"Structure-guided mutagenesis of PfARO; fluorescence microscopy of PfAIP localization","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-guided mutagenesis with localization readout, single lab","pmids":["31877322"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"Proximity-based biotinylation (BioID) was used to probe PfAIP-interacting proteins, identifying its proximal interactome at the rhoptry.","method":"Proximity-based biotinylation (BioID)","journal":"Journal of molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling without full validation of individual interactions, single lab","pmids":["31877322"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"In Toxoplasma gondii, AIP and adenylate cyclase β (ACβ) localize to a rhoptry subcompartment; in the absence of AIP, ACβ disappears from the rhoptries, placing AIP upstream of ACβ rhoptry association. P. falciparum ARO functionally complements ARO depletion in T. gondii and interacts with the same partners (including AIP), highlighting conservation of this mechanism.","method":"Conditional depletion of AIP in T. gondii; immunofluorescence; functional complementation with PfARO","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with defined localization phenotype plus cross-species functional complementation; T. gondii primary, Plasmodium finding inferred from complementation","pmids":["26769898"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfAIP (PF3D7_1136700) is one of only four P. falciparum proteins shown to localize to the cytosolic face of the rhoptry membrane, a finding cited in the context of characterizing the rhoptry cytosolic surface.","method":"Immunofluorescence / subcellular fractionation (as cited background finding)","journal":"Communications biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cited as established prior result, no new primary experiment for PfAIP in this paper","pmids":["35140336"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1136700 (AIP) is a rhoptry-associated protein in P. falciparum that localizes to the cytosolic face of the rhoptry membrane via interaction with the armadillo-repeat protein ARO; this interaction is required for correct rhoptry targeting of adenylate cyclase β, and conditional mislocalization of AIP causes a defect in red blood cell invasion."},"narrative":{"mechanistic_narrative":"PF3D7_1136700 (AIP) is a rhoptry-associated protein of Plasmodium falciparum that functions in red blood cell invasion [PMID:31877322]. AIP localizes to the rhoptries, and its conditional mislocalization produces a defect in host cell invasion, establishing an essential role in this process [PMID:31877322]. AIP is recruited to the cytosolic face of the rhoptry membrane through direct dependence on the armadillo-repeat protein ARO: structure-guided mutations in the ARO armadillo repeats mislocalize AIP, indicating that its rhoptry targeting requires the ARO interaction [PMID:31877322]. This ARO–AIP relationship is conserved across apicomplexans, as P. falciparum ARO functionally complements ARO depletion in Toxoplasma gondii and engages the same partners including AIP; in T. gondii, AIP acts upstream of adenylate cyclase β rhoptry association, since AC β is lost from the rhoptries in the absence of AIP [PMID:26769898]. Beyond this ARO-dependent rhoptry-targeting and invasion role, the AIP proximal interactome and its molecular activity have not been further characterized in the available corpus [PMID:31877322].","teleology":[{"year":2016,"claim":"Before this work it was unknown how adenylate cyclase β is anchored at the rhoptry; the study placed AIP upstream of ACβ rhoptry association and established conservation of the ARO–AIP module across apicomplexans.","evidence":"Conditional depletion of AIP in T. gondii with immunofluorescence, plus functional complementation of T. gondii ARO depletion by P. falciparum ARO","pmids":["26769898"],"confidence":"Medium","gaps":["The P. falciparum AIP–ACβ relationship is inferred from cross-species complementation, not directly demonstrated in P. falciparum","The direct biochemical nature of the AIP–ACβ link is not resolved","No structural model of the AIP–ARO interface"],"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"To determine AIP's role in P. falciparum, conditional mislocalization was used to show AIP resides at the rhoptries and is required for red blood cell invasion, defining its function in the parasite's own life cycle.","evidence":"DiCre-based conditional mislocalization with fluorescence microscopy and an invasion assay in P. falciparum","pmids":["31877322"],"confidence":"Medium","gaps":["The molecular step of invasion that AIP contributes to is not defined","Whether the invasion defect is direct or secondary to loss of other rhoptry components is unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"It was unclear what recruits AIP to the rhoptry; structure-guided ARO mutagenesis showed AIP targeting depends on direct interaction with ARO, defining the recruitment mechanism.","evidence":"Structure-guided mutagenesis of PfARO armadillo repeats with fluorescence microscopy of AIP localization in P. falciparum","pmids":["31877322"],"confidence":"Medium","gaps":["The AIP residues mediating the ARO contact are not mapped","Direct binding was inferred from localization rather than reconstituted biochemically"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"To place AIP in its molecular neighborhood, proximity biotinylation was used to sketch the AIP proximal interactome at the rhoptry.","evidence":"Proximity-based biotinylation (BioID) in P. falciparum","pmids":["31877322"],"confidence":"Low","gaps":["Individual proximity hits were not validated by reciprocal or orthogonal interaction assays","Proximity labeling does not distinguish direct partners from bystanders"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"AIP was situated among the rhoptry cytosolic-surface proteome, reinforcing its localization to the cytosolic face of the rhoptry membrane.","evidence":"Cited as an established prior result during characterization of the rhoptry cytosolic surface in P. falciparum","pmids":["35140336"],"confidence":"Low","gaps":["No new primary experiment for AIP was performed in this study","Membrane topology and mode of membrane association of AIP are not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The molecular activity of AIP itself, its validated direct binding partners beyond ARO, and the mechanistic step of invasion it enables remain unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic or biochemical activity assigned to AIP","Direct AIP interactome not validated beyond the ARO dependence","Precise contribution of AIP to the invasion mechanism unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["ARO (ARMADILLO-REPEAT PROTEIN; DIRECT INTERACTION REQUIRED FOR AIP RHOPTRY TARGETING)","ADENYLATE CYCLASE Β (AIP ACTS UPSTREAM OF ACΒ RHOPTRY ASSOCIATION IN T. GONDII)"],"other_free_text":["AIP localizes to the cytosolic face of the rhoptry membrane in P. falciparum [#4].","The ARO-dependent AIP recruitment module is conserved between P. falciparum and T. gondii, shown by cross-species functional complementation [#3].","A BioID proximal interactome of AIP has been generated but individual interactions are not validated [#2]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"26769898","id":"PMC_26769898","title":"Structural and functional dissection of Toxoplasma gondii armadillo repeats only protein.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/26769898","citation_count":27,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["AIP"],"competing_organism_flag":true,"competing_organism_match":"Toxoplasma","competing_organism_only":true},{"pmid":"31877322","id":"PMC_31877322","title":"Structural Insights Into PfARO and Characterization of its Interaction With PfAIP.","date":"2019","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31877322","citation_count":19,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfAIP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37192974","id":"","title":"Targeting an essential Plasmodium cold shock protein to block growth and transmission of malaria parasite.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37192974","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["AIP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38892332","id":"","title":"Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38892332","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["AIP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35140336","id":"","title":"Cell biological analysis reveals an essential role for Pfcerli2 in erythrocyte invasion by malaria parasites.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35140336","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["AIP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29263246","id":"","title":"Cyclic nucleotide signalling in malaria parasites.","date":"2017","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/29263246","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["AIP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"6759513","id":"","title":"Involvement of spectrin and ATP in infection of resealed erythrocyte ghosts by the human malarial parasite, Plasmodium falciparum.","date":"1982","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/6759513","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["AIP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7956,"output_tokens":1213,"usd":0.021032,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6114,"output_tokens":2406,"usd":0.04536,"stage2_stop_reason":"end_turn"},"total_usd":0.066392,"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\": \"PfAIP (PF3D7_1136700) localizes to the rhoptries in P. falciparum, and conditional mislocalization of PfAIP leads to deficient red blood cell invasion, establishing an essential role in host cell invasion.\",\n      \"method\": \"Conditional mislocalization system (DiCre-based), fluorescence microscopy\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional mislocalization with defined invasion phenotype, single lab, two orthogonal methods (localization + functional assay)\",\n      \"pmids\": [\"31877322\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PfARO armadillo repeat mutations identified by structural guidance cause mislocalization of PfAIP, indicating that PfAIP rhoptry targeting depends on direct interaction with PfARO.\",\n      \"method\": \"Structure-guided mutagenesis of PfARO; fluorescence microscopy of PfAIP localization\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided mutagenesis with localization readout, single lab\",\n      \"pmids\": [\"31877322\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Proximity-based biotinylation (BioID) was used to probe PfAIP-interacting proteins, identifying its proximal interactome at the rhoptry.\",\n      \"method\": \"Proximity-based biotinylation (BioID)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling without full validation of individual interactions, single lab\",\n      \"pmids\": [\"31877322\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Toxoplasma gondii, AIP and adenylate cyclase β (ACβ) localize to a rhoptry subcompartment; in the absence of AIP, ACβ disappears from the rhoptries, placing AIP upstream of ACβ rhoptry association. P. falciparum ARO functionally complements ARO depletion in T. gondii and interacts with the same partners (including AIP), highlighting conservation of this mechanism.\",\n      \"method\": \"Conditional depletion of AIP in T. gondii; immunofluorescence; functional complementation with PfARO\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with defined localization phenotype plus cross-species functional complementation; T. gondii primary, Plasmodium finding inferred from complementation\",\n      \"pmids\": [\"26769898\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PfAIP (PF3D7_1136700) is one of only four P. falciparum proteins shown to localize to the cytosolic face of the rhoptry membrane, a finding cited in the context of characterizing the rhoptry cytosolic surface.\",\n      \"method\": \"Immunofluorescence / subcellular fractionation (as cited background finding)\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cited as established prior result, no new primary experiment for PfAIP in this paper\",\n      \"pmids\": [\"35140336\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1136700 (AIP) is a rhoptry-associated protein in P. falciparum that localizes to the cytosolic face of the rhoptry membrane via interaction with the armadillo-repeat protein ARO; this interaction is required for correct rhoptry targeting of adenylate cyclase β, and conditional mislocalization of AIP causes a defect in red blood cell invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1136700 (AIP) is a rhoptry-associated protein of Plasmodium falciparum that functions in red blood cell invasion [#0]. AIP localizes to the rhoptries, and its conditional mislocalization produces a defect in host cell invasion, establishing an essential role in this process [#0]. AIP is recruited to the cytosolic face of the rhoptry membrane through direct dependence on the armadillo-repeat protein ARO: structure-guided mutations in the ARO armadillo repeats mislocalize AIP, indicating that its rhoptry targeting requires the ARO interaction [#1]. This ARO–AIP relationship is conserved across apicomplexans, as P. falciparum ARO functionally complements ARO depletion in Toxoplasma gondii and engages the same partners including AIP; in T. gondii, AIP acts upstream of adenylate cyclase β rhoptry association, since AC β is lost from the rhoptries in the absence of AIP [#3]. Beyond this ARO-dependent rhoptry-targeting and invasion role, the AIP proximal interactome and its molecular activity have not been further characterized in the available corpus [#2].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Before this work it was unknown how adenylate cyclase β is anchored at the rhoptry; the study placed AIP upstream of ACβ rhoptry association and established conservation of the ARO–AIP module across apicomplexans.\",\n      \"evidence\": \"Conditional depletion of AIP in T. gondii with immunofluorescence, plus functional complementation of T. gondii ARO depletion by P. falciparum ARO\",\n      \"pmids\": [\"26769898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The P. falciparum AIP–ACβ relationship is inferred from cross-species complementation, not directly demonstrated in P. falciparum\",\n        \"The direct biochemical nature of the AIP–ACβ link is not resolved\",\n        \"No structural model of the AIP–ARO interface\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"To determine AIP's role in P. falciparum, conditional mislocalization was used to show AIP resides at the rhoptries and is required for red blood cell invasion, defining its function in the parasite's own life cycle.\",\n      \"evidence\": \"DiCre-based conditional mislocalization with fluorescence microscopy and an invasion assay in P. falciparum\",\n      \"pmids\": [\"31877322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular step of invasion that AIP contributes to is not defined\",\n        \"Whether the invasion defect is direct or secondary to loss of other rhoptry components is unresolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unclear what recruits AIP to the rhoptry; structure-guided ARO mutagenesis showed AIP targeting depends on direct interaction with ARO, defining the recruitment mechanism.\",\n      \"evidence\": \"Structure-guided mutagenesis of PfARO armadillo repeats with fluorescence microscopy of AIP localization in P. falciparum\",\n      \"pmids\": [\"31877322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The AIP residues mediating the ARO contact are not mapped\",\n        \"Direct binding was inferred from localization rather than reconstituted biochemically\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"To place AIP in its molecular neighborhood, proximity biotinylation was used to sketch the AIP proximal interactome at the rhoptry.\",\n      \"evidence\": \"Proximity-based biotinylation (BioID) in P. falciparum\",\n      \"pmids\": [\"31877322\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Individual proximity hits were not validated by reciprocal or orthogonal interaction assays\",\n        \"Proximity labeling does not distinguish direct partners from bystanders\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"AIP was situated among the rhoptry cytosolic-surface proteome, reinforcing its localization to the cytosolic face of the rhoptry membrane.\",\n      \"evidence\": \"Cited as an established prior result during characterization of the rhoptry cytosolic surface in P. falciparum\",\n      \"pmids\": [\"35140336\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No new primary experiment for AIP was performed in this study\",\n        \"Membrane topology and mode of membrane association of AIP are not defined\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular activity of AIP itself, its validated direct binding partners beyond ARO, and the mechanistic step of invasion it enables remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No enzymatic or biochemical activity assigned to AIP\",\n        \"Direct AIP interactome not validated beyond the ARO dependence\",\n        \"Precise contribution of AIP to the invasion mechanism unresolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0020008\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ARO (armadillo-repeat protein; direct interaction required for AIP rhoptry targeting)\",\n      \"adenylate cyclase β (AIP acts upstream of ACβ rhoptry association in T. gondii)\"\n    ],\n    \"other_free_text\": [\n      \"AIP localizes to the cytosolic face of the rhoptry membrane in P. falciparum [#4].\",\n      \"The ARO-dependent AIP recruitment module is conserved between P. falciparum and T. gondii, shown by cross-species functional complementation [#3].\",\n      \"A BioID proximal interactome of AIP has been generated but individual interactions are not validated [#2].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1136700","name":null,"product":"armadillo-interacting protein AIP","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0911900","name":null,"product":"armadillo-interacting protein AIP, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0934900","name":null,"product":"armadillo-interacting protein AIP, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"AIP","evaluation":null}