{"gene":"PF3D7_1355600","run_date":"2026-09-08T16:55:55+00:00","timeline":{"discoveries":[{"year":2017,"finding":"PIP1 (PF3D7_1355600) is a component of the gametocyte inner membrane complex (IMC) of P. falciparum. Genetic disruption of PIP1 ablates gametocyte elongation and prevents formation of transmission-ready mature gametocytes, accompanied by failure to form an enveloping IMC and marked swelling of the digestive vacuole, indicating PIP1 is required for correct membrane trafficking during sexual stage development.","method":"Super-resolution optical and electron microscopy for ultrastructure; genetic disruption (knockout) with phenotypic readout (elongation failure, IMC absence, digestive vacuole swelling); immunoprecipitation and mass spectrometry for interactome","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct genetic disruption with multiple specific phenotypic readouts (morphology, IMC formation, organelle swelling) combined with super-resolution and electron microscopy, single lab but orthogonal methods","pmids":["28985225"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"PIP1 (PF3D7_1355600, referred to as PfPhIP in this study) is an uncharacterized protein that associates with the PhIL1 complex in the inner membrane complex of P. falciparum merozoites. Conditional downregulation of PIP1 results in significant defects in merozoite segmentation, abrogation of merozoite reorientation/gliding, and failure to invade host erythrocytes, while initial attachment to host RBCs was not affected.","method":"Experimental genetics (conditional knockdown/knockdown by inducible system); invasion assay; reorientation/gliding assays; co-immunoprecipitation with PhIL1 to establish complex membership","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockdown with multiple distinct functional readouts (segmentation, reorientation, invasion) and co-IP to establish complex membership, single lab with orthogonal assays","pmids":["34324609"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PIP1 (PF3D7_1355600) is a component of the PhIL1-associated complex residing in the inner membrane complex of P. falciparum, where it is required for gametocyte elongation and IMC formation during sexual stages, and for merozoite segmentation, reorientation/gliding, and erythrocyte invasion during asexual stages, likely through a role in correct membrane trafficking and anchoring of IMC-associated machinery."},"narrative":{"mechanistic_narrative":"PIP1 (PF3D7_1355600) is a component of the PhIL1-associated complex within the inner membrane complex (IMC) of Plasmodium falciparum, required for correct membrane trafficking and IMC formation across both sexual and asexual stages [PMID:28985225, PMID:34324609]. In gametocytes, genetic disruption of PIP1 ablates cell elongation and prevents formation of transmission-ready mature gametocytes, with failure to form an enveloping IMC and marked swelling of the digestive vacuole [PMID:28985225]. In merozoites, PIP1 associates with the PhIL1 complex, and its conditional downregulation causes defects in merozoite segmentation, abrogates reorientation/gliding, and blocks erythrocyte invasion while leaving initial attachment to red blood cells intact [PMID:34324609]. Beyond its membership in the PhIL1 complex and these stage-specific IMC and invasion phenotypes, no further molecular mechanism for PIP1 has been characterized in the available corpus.","teleology":[{"year":2017,"claim":"Establishing whether PIP1 has a role in sexual-stage development, its disruption revealed a requirement for gametocyte maturation and IMC biogenesis, implicating it in membrane trafficking during transmission-stage differentiation.","evidence":"Genetic knockout with ultrastructural readout by super-resolution and electron microscopy, plus immunoprecipitation/mass spectrometry, in P. falciparum gametocytes","pmids":["28985225"],"confidence":"High","gaps":["The molecular activity of PIP1 within the IMC is not defined","How PIP1 loss mechanistically causes digestive vacuole swelling is unresolved","The direct binding partners of PIP1 versus co-purifying complex members are not distinguished"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"Extending PIP1's role to asexual blood stages, conditional knockdown established it as a PhIL1-complex member required for merozoite segmentation, reorientation/gliding, and invasion but not initial attachment, separating its function from the earliest adhesion step.","evidence":"Conditional knockdown with invasion and reorientation/gliding assays and co-immunoprecipitation with PhIL1 in P. falciparum merozoites","pmids":["34324609"],"confidence":"High","gaps":["Whether PIP1 acts structurally or as a trafficking adaptor within the PhIL1 complex is unknown","The stoichiometry and architecture of PIP1 within the PhIL1 complex is not resolved","No structural model or defined molecular activity is available"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The biochemical activity by which PIP1 contributes to IMC formation and membrane trafficking, and its direct molecular partners within the PhIL1 complex, remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No enzymatic or structural activity assigned to PIP1","Direct versus indirect interactions within the PhIL1 complex not mapped","Mechanism linking PIP1 to reorientation/gliding is not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PhIL1-associated complex"],"partners":["PHIL1"],"other_free_text":["Required for gametocyte elongation and IMC formation during sexual-stage development [#0]","Required for merozoite segmentation, reorientation/gliding, and erythrocyte invasion, but dispensable for initial attachment to red blood cells [#1]","Disruption causes swelling of the digestive vacuole in gametocytes [#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":["PIP1","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":767,"usd":0.013983,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5439,"output_tokens":1609,"usd":0.03371,"stage2_stop_reason":"end_turn"},"total_usd":0.0,"stage1_batch_id":"msgbatch_01BW7vvc7h5iV39oJ1MHMzXw","stage2_batch_id":"msgbatch_01Kh5HbgbPXepNfNCbktYkSD","note":"batch pricing = 50% of standard","skipped":true},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"PIP1 (PF3D7_1355600) is a component of the gametocyte inner membrane complex (IMC) of P. falciparum. Genetic disruption of PIP1 ablates gametocyte elongation and prevents formation of transmission-ready mature gametocytes, accompanied by failure to form an enveloping IMC and marked swelling of the digestive vacuole, indicating PIP1 is required for correct membrane trafficking during sexual stage development.\",\n      \"method\": \"Super-resolution optical and electron microscopy for ultrastructure; genetic disruption (knockout) with phenotypic readout (elongation failure, IMC absence, digestive vacuole swelling); immunoprecipitation and mass spectrometry for interactome\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic disruption with multiple specific phenotypic readouts (morphology, IMC formation, organelle swelling) combined with super-resolution and electron microscopy, single lab but orthogonal methods\",\n      \"pmids\": [\"28985225\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIP1 (PF3D7_1355600, referred to as PfPhIP in this study) is an uncharacterized protein that associates with the PhIL1 complex in the inner membrane complex of P. falciparum merozoites. Conditional downregulation of PIP1 results in significant defects in merozoite segmentation, abrogation of merozoite reorientation/gliding, and failure to invade host erythrocytes, while initial attachment to host RBCs was not affected.\",\n      \"method\": \"Experimental genetics (conditional knockdown/knockdown by inducible system); invasion assay; reorientation/gliding assays; co-immunoprecipitation with PhIL1 to establish complex membership\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockdown with multiple distinct functional readouts (segmentation, reorientation, invasion) and co-IP to establish complex membership, single lab with orthogonal assays\",\n      \"pmids\": [\"34324609\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PIP1 (PF3D7_1355600) is a component of the PhIL1-associated complex residing in the inner membrane complex of P. falciparum, where it is required for gametocyte elongation and IMC formation during sexual stages, and for merozoite segmentation, reorientation/gliding, and erythrocyte invasion during asexual stages, likely through a role in correct membrane trafficking and anchoring of IMC-associated machinery.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIP1 (PF3D7_1355600) is a component of the PhIL1-associated complex within the inner membrane complex (IMC) of Plasmodium falciparum, required for correct membrane trafficking and IMC formation across both sexual and asexual stages [#0, #1]. In gametocytes, genetic disruption of PIP1 ablates cell elongation and prevents formation of transmission-ready mature gametocytes, with failure to form an enveloping IMC and marked swelling of the digestive vacuole [#0]. In merozoites, PIP1 associates with the PhIL1 complex, and its conditional downregulation causes defects in merozoite segmentation, abrogates reorientation/gliding, and blocks erythrocyte invasion while leaving initial attachment to red blood cells intact [#1]. Beyond its membership in the PhIL1 complex and these stage-specific IMC and invasion phenotypes, no further molecular mechanism for PIP1 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing whether PIP1 has a role in sexual-stage development, its disruption revealed a requirement for gametocyte maturation and IMC biogenesis, implicating it in membrane trafficking during transmission-stage differentiation.\",\n      \"evidence\": \"Genetic knockout with ultrastructural readout by super-resolution and electron microscopy, plus immunoprecipitation/mass spectrometry, in P. falciparum gametocytes\",\n      \"pmids\": [\"28985225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular activity of PIP1 within the IMC is not defined\",\n        \"How PIP1 loss mechanistically causes digestive vacuole swelling is unresolved\",\n        \"The direct binding partners of PIP1 versus co-purifying complex members are not distinguished\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending PIP1's role to asexual blood stages, conditional knockdown established it as a PhIL1-complex member required for merozoite segmentation, reorientation/gliding, and invasion but not initial attachment, separating its function from the earliest adhesion step.\",\n      \"evidence\": \"Conditional knockdown with invasion and reorientation/gliding assays and co-immunoprecipitation with PhIL1 in P. falciparum merozoites\",\n      \"pmids\": [\"34324609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PIP1 acts structurally or as a trafficking adaptor within the PhIL1 complex is unknown\",\n        \"The stoichiometry and architecture of PIP1 within the PhIL1 complex is not resolved\",\n        \"No structural model or defined molecular activity is available\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity by which PIP1 contributes to IMC formation and membrane trafficking, and its direct molecular partners within the PhIL1 complex, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No enzymatic or structural activity assigned to PIP1\",\n        \"Direct versus indirect interactions within the PhIL1 complex not mapped\",\n        \"Mechanism linking PIP1 to reorientation/gliding is not established\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"inner membrane complex\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"erythrocyte invasion\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"gametocyte development\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"PhIL1-associated complex\"\n    ],\n    \"partners\": [\n      \"PhIL1\"\n    ],\n    \"other_free_text\": [\n      \"Required for gametocyte elongation and IMC formation during sexual-stage development [#0]\",\n      \"Required for merozoite segmentation, reorientation/gliding, and erythrocyte invasion, but dispensable for initial attachment to red blood cells [#1]\",\n      \"Disruption causes swelling of the digestive vacuole in gametocytes [#0]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1355600","name":null,"product":"PhIL1 interacting protein PIP1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1115900","name":null,"product":"PhIL1 interacting protein PIP1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PIP1","evaluation":null}