{"gene":"PF3D7_1430800","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2021,"finding":"PIP3 (PfPhIP, PhIL1 Interacting Protein, PF3D7_1430800) was identified as a component of a novel PhIL1-associated protein complex co-existing with the glideosome motor complex in the inner membrane complex of P. falciparum merozoites. Genetic downregulation of PIP3 resulted in significant defects in merozoite segmentation, abrogation of reorientation/gliding after initial RBC attachment, and failure to invade host erythrocytes, while initial attachment with host RBCs was not affected.","method":"Experimental genetics (conditional knockdown), immunoprecipitation/interaction studies, invasion and reorientation assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with specific cellular phenotype readouts (segmentation, reorientation, invasion) in a single lab using multiple orthogonal assays","pmids":["34324609"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"PhIL1 (the binding partner of PIP3/PF3D7_1430800) was identified by immunoprecipitation and mass spectrometry to interact with known and new components of the gametocyte IMC, and PIP1 (a distinct protein characterized alongside PhIL1) was shown to be required for gametocyte elongation. PIP3 itself was identified as a PhIL1-interacting protein by the immunoprecipitation/mass spectrometry approach reported in this study.","method":"Immunoprecipitation and mass spectrometry, super-resolution and electron microscopy, genetic disruption","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation with mass spectrometry identifying PIP3 as a PhIL1-interacting IMC component, single lab","pmids":["28985225"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"BioID proximity-labelling using PhIL1 as bait in asexual blood-stage P. falciparum parasites enriched PIP3 (PF3D7_1430800) among candidate IMC-associated proteins, supporting its localization to or near the IMC in asexual stages.","method":"BioID proximity-dependent biotinylation, mass spectrometry, endogenous GFP-tagging validation","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID proteomics with GFP-tagging validation, single lab, but PIP3 specifically identified as enriched candidate","pmids":["33830607"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PIP3 (PF3D7_1430800) is a PhIL1-interacting protein that localizes to the inner membrane complex of P. falciparum merozoites as part of a novel PhIL1-associated complex; its loss causes defects in merozoite segmentation and abrogates merozoite reorientation/gliding after initial erythrocyte attachment, thereby blocking host cell invasion without affecting initial attachment."},"narrative":{"mechanistic_narrative":"PIP3 (PF3D7_1430800) is a PhIL1-interacting protein of the Plasmodium falciparum inner membrane complex (IMC) that is required for merozoite morphogenesis and host-cell invasion [PMID:34324609, PMID:28985225]. It was defined as a component of a novel PhIL1-associated protein complex that co-exists with the glideosome motor at the merozoite IMC, and independent BioID proximity-labelling using PhIL1 as bait enriched PIP3 in asexual blood-stage parasites, consistent with its IMC localization across stages [PMID:34324609, PMID:33830607]. Conditional downregulation of PIP3 causes defective merozoite segmentation and, at the level of invasion, abrogates reorientation/gliding following initial erythrocyte attachment while leaving initial attachment intact, placing PIP3 downstream of attachment in the invasion sequence [PMID:34324609]. Beyond its PhIL1 association, IMC localization, and knockdown phenotype, no molecular activity or direct downstream effector of PIP3 has been characterized in the available corpus.","teleology":[{"year":2017,"claim":"The first question was whether PIP3 associates physically with the IMC machinery, answered by identifying it as a binding partner of the IMC protein PhIL1.","evidence":"Immunoprecipitation and mass spectrometry using PhIL1 as bait in P. falciparum gametocytes, with super-resolution and electron microscopy of the complex","pmids":["28985225"],"confidence":"Medium","gaps":["Does not establish whether PIP3 binds PhIL1 directly or through other complex members","No functional role assigned to PIP3 itself in this study","Interaction detected in gametocytes, not yet in asexual stages"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"A second question was whether the PhIL1-PIP3 association extends to asexual blood stages, addressed by proximity-labelling confirming PIP3 near PhIL1 at the asexual IMC.","evidence":"BioID proximity-dependent biotinylation with PhIL1 as bait, mass spectrometry, and endogenous GFP-tagging validation in asexual blood-stage P. falciparum","pmids":["33830607"],"confidence":"Medium","gaps":["Proximity labelling does not distinguish direct binding from spatial neighbourhood","Does not assign a function to PIP3 in asexual stages"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"The central functional question — what role PIP3 plays in the parasite life cycle — was answered by showing it is required for merozoite segmentation and for the gliding/reorientation step of erythrocyte invasion.","evidence":"Conditional knockdown with immunoprecipitation-based complex characterization and invasion/reorientation assays in P. falciparum merozoites","pmids":["34324609"],"confidence":"Medium","gaps":["Molecular activity of PIP3 (enzymatic or structural) not defined","Mechanism linking PIP3 loss to reorientation failure unresolved","Whether the segmentation defect is upstream of or independent from the invasion defect not distinguished"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"It remains unknown what biochemical activity PIP3 contributes to the PhIL1 complex and how its loss mechanistically couples to failed merozoite reorientation and gliding.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No molecular/enzymatic activity assigned to PIP3","No structural model or direct-binding map of PIP3 within the PhIL1 complex","Downstream effectors mediating the reorientation/gliding phenotype unidentified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PhIL1-associated IMC protein complex"],"partners":["PHIL1"],"other_free_text":["PIP3 downregulation abrogates merozoite reorientation/gliding after initial erythrocyte attachment while leaving initial attachment unaffected [#0]","PIP3 was enriched by BioID proximity-labelling with PhIL1 as bait in asexual blood-stage parasites [#2]","The PhIL1-associated complex co-exists with the glideosome motor complex at the merozoite IMC [#0]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"28985225","id":"PMC_28985225","title":"Disrupting assembly of the inner membrane complex blocks Plasmodium falciparum sexual stage development.","date":"2017","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/28985225","citation_count":65,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PhIL1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33830607","id":"PMC_33830607","title":"Identification of novel inner membrane complex and apical annuli proteins of the malaria parasite Plasmodium falciparum.","date":"2021","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33830607","citation_count":33,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PhIL1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29138437","id":"PMC_29138437","title":"Photosensitized INA-Labelled protein 1 (PhIL1) is novel component of the inner membrane complex and is required for Plasmodium parasite development.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29138437","citation_count":25,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PhIL1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34324609","id":"PMC_34324609","title":"Plasmodium falciparum PhIL1-associated complex plays an essential role in merozoite reorientation and invasion of host erythrocytes.","date":"2021","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/34324609","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PhIL1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39576115","id":"PMC_39576115","title":"An inner membrane complex protein IMC1g in Plasmodium berghei is involved in asexual stage schizogony and parasite transmission.","date":"2024","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/39576115","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PhIL1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5487,"output_tokens":956,"usd":0.0154,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5702,"output_tokens":1933,"usd":0.038418,"stage2_stop_reason":"end_turn"},"total_usd":0.053818,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"PIP3 (PfPhIP, PhIL1 Interacting Protein, PF3D7_1430800) was identified as a component of a novel PhIL1-associated protein complex co-existing with the glideosome motor complex in the inner membrane complex of P. falciparum merozoites. Genetic downregulation of PIP3 resulted in significant defects in merozoite segmentation, abrogation of reorientation/gliding after initial RBC attachment, and failure to invade host erythrocytes, while initial attachment with host RBCs was not affected.\",\n      \"method\": \"Experimental genetics (conditional knockdown), immunoprecipitation/interaction studies, invasion and reorientation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with specific cellular phenotype readouts (segmentation, reorientation, invasion) in a single lab using multiple orthogonal assays\",\n      \"pmids\": [\"34324609\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PhIL1 (the binding partner of PIP3/PF3D7_1430800) was identified by immunoprecipitation and mass spectrometry to interact with known and new components of the gametocyte IMC, and PIP1 (a distinct protein characterized alongside PhIL1) was shown to be required for gametocyte elongation. PIP3 itself was identified as a PhIL1-interacting protein by the immunoprecipitation/mass spectrometry approach reported in this study.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry, super-resolution and electron microscopy, genetic disruption\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation with mass spectrometry identifying PIP3 as a PhIL1-interacting IMC component, single lab\",\n      \"pmids\": [\"28985225\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BioID proximity-labelling using PhIL1 as bait in asexual blood-stage P. falciparum parasites enriched PIP3 (PF3D7_1430800) among candidate IMC-associated proteins, supporting its localization to or near the IMC in asexual stages.\",\n      \"method\": \"BioID proximity-dependent biotinylation, mass spectrometry, endogenous GFP-tagging validation\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID proteomics with GFP-tagging validation, single lab, but PIP3 specifically identified as enriched candidate\",\n      \"pmids\": [\"33830607\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PIP3 (PF3D7_1430800) is a PhIL1-interacting protein that localizes to the inner membrane complex of P. falciparum merozoites as part of a novel PhIL1-associated complex; its loss causes defects in merozoite segmentation and abrogates merozoite reorientation/gliding after initial erythrocyte attachment, thereby blocking host cell invasion without affecting initial attachment.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PIP3 (PF3D7_1430800) is a PhIL1-interacting protein of the Plasmodium falciparum inner membrane complex (IMC) that is required for merozoite morphogenesis and host-cell invasion [#0, #1]. It was defined as a component of a novel PhIL1-associated protein complex that co-exists with the glideosome motor at the merozoite IMC, and independent BioID proximity-labelling using PhIL1 as bait enriched PIP3 in asexual blood-stage parasites, consistent with its IMC localization across stages [#0, #2]. Conditional downregulation of PIP3 causes defective merozoite segmentation and, at the level of invasion, abrogates reorientation/gliding following initial erythrocyte attachment while leaving initial attachment intact, placing PIP3 downstream of attachment in the invasion sequence [#0]. Beyond its PhIL1 association, IMC localization, and knockdown phenotype, no molecular activity or direct downstream effector of PIP3 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"The first question was whether PIP3 associates physically with the IMC machinery, answered by identifying it as a binding partner of the IMC protein PhIL1.\",\n      \"evidence\": \"Immunoprecipitation and mass spectrometry using PhIL1 as bait in P. falciparum gametocytes, with super-resolution and electron microscopy of the complex\",\n      \"pmids\": [\"28985225\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Does not establish whether PIP3 binds PhIL1 directly or through other complex members\",\n        \"No functional role assigned to PIP3 itself in this study\",\n        \"Interaction detected in gametocytes, not yet in asexual stages\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A second question was whether the PhIL1-PIP3 association extends to asexual blood stages, addressed by proximity-labelling confirming PIP3 near PhIL1 at the asexual IMC.\",\n      \"evidence\": \"BioID proximity-dependent biotinylation with PhIL1 as bait, mass spectrometry, and endogenous GFP-tagging validation in asexual blood-stage P. falciparum\",\n      \"pmids\": [\"33830607\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Proximity labelling does not distinguish direct binding from spatial neighbourhood\",\n        \"Does not assign a function to PIP3 in asexual stages\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The central functional question — what role PIP3 plays in the parasite life cycle — was answered by showing it is required for merozoite segmentation and for the gliding/reorientation step of erythrocyte invasion.\",\n      \"evidence\": \"Conditional knockdown with immunoprecipitation-based complex characterization and invasion/reorientation assays in P. falciparum merozoites\",\n      \"pmids\": [\"34324609\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular activity of PIP3 (enzymatic or structural) not defined\",\n        \"Mechanism linking PIP3 loss to reorientation failure unresolved\",\n        \"Whether the segmentation defect is upstream of or independent from the invasion defect not distinguished\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what biochemical activity PIP3 contributes to the PhIL1 complex and how its loss mechanistically couples to failed merozoite reorientation and gliding.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No molecular/enzymatic activity assigned to PIP3\",\n        \"No structural model or direct-binding map of PIP3 within the PhIL1 complex\",\n        \"Downstream effectors mediating the reorientation/gliding phenotype unidentified\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"inner membrane complex\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"host erythrocyte invasion\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"merozoite segmentation/morphogenesis\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"PhIL1-associated IMC protein complex\"],\n    \"partners\": [\"PhIL1\"],\n    \"other_free_text\": [\n      \"PIP3 downregulation abrogates merozoite reorientation/gliding after initial erythrocyte attachment while leaving initial attachment unaffected [#0]\",\n      \"PIP3 was enriched by BioID proximity-labelling with PhIL1 as bait in asexual blood-stage parasites [#2]\",\n      \"The PhIL1-associated complex co-exists with the glideosome motor complex at the merozoite IMC [#0]\"\n    ]\n  }\n}\n```","audit_flag":{"gene":"PF3D7_1430800","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 3 of 3 cited papers name other catalogue genes (PF3D7_0109000, PF3D7_1355600, PF3D7_1343700). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1430800","name":null,"product":"PhIL1 interacting protein PIP3","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1013900","name":null,"product":"PhIL1 interacting protein PIP3, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1327900","name":null,"product":"PhIL1 interacting protein PIP3, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PIP3","evaluation":null}