{"gene":"PF3D7_1320600","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2009,"finding":"RAB11a (PF3D7_1320600) is required for the final step of apicomplexan cytokinesis: delivery of new plasma membrane to daughter cells. Functional RAB11a was found in association with Myosin-Tail-Interacting-Protein (MTIP/MLC1), a member of the glideosome motor complex. Ablation of RAB11a function resulted in daughter parasites with an incompletely formed Inner Membrane Complex (IMC), causing a block at a late stage of cell division, phenocopied by expression of a myosin A tail-only dominant-negative mutant.","method":"Dominant-negative RAB11a expression, co-immunoprecipitation with MTIP/MLC1, fluorescence microscopy of IMC assembly, genetic epistasis with myosin A tail mutant","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction (Co-IP with MTIP), dominant-negative loss-of-function with defined cellular phenotype, genetic epistasis with myosin A mutant, multiple orthogonal methods in single study","pmids":["19165333"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Toxoplasma gondii","strain":""}]},{"year":2014,"finding":"Crystal structures of PI4KIIIβ bound to Rab11a (without and with the Rab11 effector FIP3) revealed that the Rab11a–PI4KIIIβ interface is distinct from known Rab complex structures and does not involve the switch regions typically used by GTPase effectors, providing a mechanism for simultaneous recruitment of Rab11a and its effectors on PI4P-enriched membranes.","method":"X-ray crystallography of PI4KIIIβ–Rab11a binary and ternary (with FIP3) complexes; structural comparison with known Rab complex structures","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures of the complex with and without effector, defining a novel interaction interface with structural validation","pmids":["24876499"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"PfRAB11A (PF3D7_1320600) shows a distinct subcellular distribution compared to PfRab1A, as demonstrated by generation of specific antisera and immunolocalization in P. falciparum-infected erythrocytes.","method":"Generation of specific antisera; immunofluorescence/immunolocalization of PfRab11A versus PfRab1A in infected erythrocytes","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single-lab localization using specific antisera, no functional consequence reported","pmids":["12657463"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"PfRAB11a (PF3D7_1320600) possesses intrinsic GTPase enzymatic activity, confirmed by an orthogonal enzyme assay; small-molecule fragments and the natural product arborside E were identified as weak binders to PfRAB11a by ESI-FTICR-MS screening.","method":"ESI-FTICR-MS binding assay; orthogonal GTPase enzyme activity assay; titration experiments confirming binding","journal":"Journal of biomolecular screening","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro GTPase enzyme assay confirming enzymatic activity, single lab, confirmatory rather than mechanistically novel","pmids":["26773071"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"PbRAB11A is essential for zygote-to-ookinete morphological maturation in P. berghei. Promoter-swap-mediated downregulation of PbRAB11A had no effect on gamete production, fertility, meiosis, mitosis, or establishment of IMC/apical complex polarity, but almost totally inhibited the zygote-to-ookinete transition, leaving parasites spherical and immotile. PbRAB11A loss also impaired secretion and distribution of microneme cargo, implicating RAB11A in endosome-mediated delivery of plasma membrane components.","method":"Promoter swap strategy for conditional downregulation of PbRAB11A in gametocytes/zygotes; fluorescence microscopy of IMC and apical complex; mosquito transmission assays; assessment of microneme cargo secretion/distribution","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic knockdown with multiple orthogonal phenotypic readouts (morphology, polarity markers, microneme secretion, transmission), single lab but comprehensive analysis","pmids":["32463831"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"finding":"Functional Rab11a in the host hepatocyte is critical for the ability of P. berghei liver stage parasites to induce fragmentation of the host cell Golgi into miniaturized stacks, a process that increases surface interactions with the parasitophorous vacuolar membrane. Expression of dominant-negative Rab11a (among other dominant-negative Rab GTPases) resulted in developmental delay and diminished survival of liver stage parasites.","method":"Dominant-negative Rab GTPase expression in host hepatocytes; dynamic fluorescence-based live imaging of Golgi fragmentation; parasite developmental assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — dominant-negative expression with live-imaging phenotype, but the Rab11a tested here is the host cell (hepatocyte) Rab11a, not the parasite's own RAB11a; attribution is to parasite-induced manipulation of host Rab11a","pmids":["34013963"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2024,"finding":"In P. yoelii ookinetes, RAB11A interacts with dynein heavy chain 3 (DHC3) at subpellicular microtubules (SPMTs) in a DHC3-dependent manner, functioning as a receptor/cargo label for SPMT-dynein-driven transport. Disruption of RAB11A phenocopied DHC3 deficiency, impairing ookinete morphogenesis, apical organelle formation/localization, and mosquito infectivity.","method":"Co-immunoprecipitation of RAB11A with DHC3; genetic disruption of RAB11A; fluorescence microscopy of ookinete morphogenesis and apical organelles; mosquito infection assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction with DHC3, genetic knockout with defined cellular phenotype, epistasis with DHC3 disruption, single lab","pmids":["39366980"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]}],"current_model":"RAB11a (PF3D7_1320600) is a small GTPase that mediates vesicular trafficking of plasma membrane and microneme cargo during parasite cell division and morphogenesis: it physically associates with the glideosome component MTIP/MLC1 and with dynein heavy chain DHC3 at subpellicular microtubules, is required for IMC maturation and daughter cell budding during asexual replication, drives ookinete morphological maturation (including microneme secretion) in mosquito stages, and structurally engages PI4KIIIβ through a switch-region-independent interface that enables simultaneous recruitment of Rab11a and its effectors on PI4P-enriched membranes."},"narrative":{"mechanistic_narrative":"RAB11a (PF3D7_1320600) is a small GTPase with confirmed intrinsic GTPase activity [PMID:26773071] that governs membrane and cargo trafficking during Plasmodium cell division and morphogenesis [PMID:19165333, PMID:32463831]. In P. falciparum asexual blood stages it executes the final step of cytokinesis by delivering new plasma membrane to nascent daughter parasites: functional RAB11a associates with the glideosome motor component MTIP/MLC1, and its loss produces daughter cells with an incompletely formed Inner Membrane Complex, phenocopied by a myosin A tail dominant-negative mutant [PMID:19165333]. In mosquito stages, RAB11a orthologs drive morphological maturation: in P. berghei it is essential for the zygote-to-ookinete transition and for secretion and distribution of microneme cargo, without affecting fertility, meiosis, mitosis, or apical/IMC polarity establishment [PMID:32463831], and in P. yoelii ookinetes it acts as a cargo receptor for subpellicular-microtubule dynein-driven transport through a DHC3-dependent interaction, with its disruption impairing ookinete morphogenesis and apical organelle formation [PMID:39366980]. Structurally, Rab11a engages PI4KIIIβ through an interface distinct from the switch regions normally used by GTPase effectors, permitting simultaneous recruitment of Rab11a and its effectors such as FIP3 on PI4P-enriched membranes [PMID:24876499].","teleology":[{"year":2003,"claim":"Establishing that PfRAB11A occupies a subcellular compartment distinct from other parasite Rab GTPases was the first step toward assigning it a dedicated trafficking role.","evidence":"Specific antisera and immunolocalization comparing PfRab11A versus PfRab1A in infected erythrocytes","pmids":["12657463"],"confidence":"Medium","gaps":["No functional consequence of the localization was tested","Does not identify the trafficking pathway or cargo"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"The question of what completes apicomplexan cytokinesis was answered by placing RAB11a at the final membrane-delivery step, linking vesicular trafficking to the glideosome motor machinery.","evidence":"Dominant-negative RAB11a expression, Co-IP with MTIP/MLC1, IMC imaging, and genetic epistasis with a myosin A tail mutant","pmids":["19165333"],"confidence":"High","gaps":["Direct membrane cargo carried by RAB11a not molecularly defined","Nature of the RAB11a–MTIP association (direct vs. indirect) not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Toxoplasma gondii","strain":""}]},{"year":2014,"claim":"How Rab11a can bind an effector kinase and its downstream effectors at once was answered structurally, revealing a switch-region-independent interface with PI4KIIIβ.","evidence":"X-ray crystallography of PI4KIIIβ–Rab11a binary and PI4KIIIβ–Rab11a–FIP3 ternary complexes","pmids":["24876499"],"confidence":"High","gaps":["In vivo relevance of this interface to parasite trafficking not demonstrated","Whether the PI4KIIIβ interaction operates in the same pathway as MTIP-linked cytokinesis is untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Whether PfRAB11a is a bona fide enzyme was confirmed by direct demonstration of intrinsic GTPase activity, and initial chemical-probe binders were identified.","evidence":"ESI-FTICR-MS fragment screening plus an orthogonal GTPase enzyme activity assay","pmids":["26773071"],"confidence":"Medium","gaps":["Identified binders are weak with no demonstrated inhibitory or cellular effect","GDP/GTP cycling regulators (GEF/GAP) not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"The role of RAB11A in mosquito stages was defined by showing it is required specifically for zygote-to-ookinete morphogenesis and microneme cargo delivery rather than for the preceding sexual/mitotic events.","evidence":"Promoter-swap conditional downregulation of PbRAB11A with morphology, polarity-marker, microneme-secretion, and transmission readouts","pmids":["32463831"],"confidence":"High","gaps":["Molecular identity of the delivered plasma membrane/microneme cargo not defined","Effector or motor partner in ookinetes not identified in this study"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"claim":"This study concerns host hepatocyte Rab11a co-opted by the parasite, not parasite RAB11a, establishing that parasite-induced host Golgi fragmentation and liver-stage development depend on host Rab11a function.","evidence":"Dominant-negative Rab GTPase expression in host hepatocytes with live imaging of Golgi fragmentation and parasite developmental assays","pmids":["34013963"],"confidence":"Medium","gaps":["Attribution is to host-cell Rab11a, not the parasite's PF3D7_1320600","Does not establish a role for parasite RAB11a in the liver stage"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2024,"claim":"How RAB11A links cargo to the cytoskeletal transport machinery in ookinetes was answered by identifying it as a DHC3-dependent cargo label for subpellicular-microtubule dynein-driven transport.","evidence":"Co-IP of RAB11A with DHC3, genetic disruption, ookinete morphogenesis/apical-organelle imaging, and mosquito infection assays with DHC3 epistasis","pmids":["39366980"],"confidence":"Medium","gaps":["Directness of the RAB11A–DHC3 interaction not structurally established","How microtubule-based transport integrates with the MTIP/glideosome pathway seen in blood stages is unknown"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":null,"claim":"The molecular cargo carried by parasite RAB11a and the GEF/GAP and effector network that spatially controls its GTP cycling across life-cycle stages remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No RAB11a-specific membrane cargo molecularly identified","No parasite GEF/GAP regulators characterized","Reconciliation of glideosome-linked (blood stage) and dynein-linked (ookinete) roles unresolved"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["MTIP/MLC1 (GLIDEOSOME MYOSIN TAIL-INTERACTING PROTEIN) [#0]","PI4KIIIΒ [#1]","FIP3 (RAB11 EFFECTOR) [#1]","DYNEIN HEAVY CHAIN 3 / DHC3 [#6]"],"other_free_text":["Required for delivery of new plasma membrane and completion of IMC assembly during daughter-cell budding in P. falciparum asexual stages [#0].","Essential for zygote-to-ookinete morphological maturation and microneme cargo secretion/distribution in P. berghei [#4].","Acts as a cargo receptor for subpellicular-microtubule dynein-driven transport in P. yoelii ookinetes [#6].","Engages PI4KIIIβ via an interface independent of the GTPase switch regions, enabling simultaneous effector recruitment on PI4P-enriched membranes [#1].","Weak small-molecule and natural-product (arborside E) binders identified by MS screening [#3].","Discovery #5 concerns host hepatocyte Rab11a co-opted by the parasite, not the parasite's own PF3D7_1320600."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"24876499","id":"PMC_24876499","title":"Structures of PI4KIIIβ complexes show simultaneous recruitment of Rab11 and its effectors.","date":"2014","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24876499","citation_count":125,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RAB11a","Rab11a"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"19165333","id":"PMC_19165333","title":"Rab11A-controlled assembly of the inner membrane complex is required for completion of apicomplexan cytokinesis.","date":"2009","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/19165333","citation_count":96,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RAB11a","Rab11a"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12657463","id":"PMC_12657463","title":"The Plasmodium falciparum family of Rab GTPases.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12657463","citation_count":74,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfRAB11a","PfRab11a"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34013963","id":"PMC_34013963","title":"Hijacking of the host cell Golgi by Plasmodium berghei liver stage parasites.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34013963","citation_count":22,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RAB11a","Rab11a"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26773071","id":"PMC_26773071","title":"Bioaffinity Mass Spectrometry Screening.","date":"2016","source":"Journal of biomolecular screening","url":"https://pubmed.ncbi.nlm.nih.gov/26773071","citation_count":19,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RAB11a","Rab11a","PfRAB11a","PfRab11a"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"8682193","id":"PMC_8682193","title":"Plasmodium falciparum: the small GTPase rab11.","date":"1996","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/8682193","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39366980","id":"PMC_39366980","title":"A subpellicular microtubule dynein transport machinery regulates ookinete morphogenesis for mosquito transmission of Plasmodium yoelii.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39366980","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RAB11a","Rab11a"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32463831","id":"PMC_32463831","title":"Zygote morphogenesis but not the establishment of cell polarity in Plasmodium berghei is controlled by the small GTPase, RAB11A.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/32463831","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RAB11a","Rab11a","PbRAB11a","PbRab11a"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6211,"output_tokens":2311,"usd":0.026649,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7627,"output_tokens":3423,"usd":0.061855,"stage2_stop_reason":"end_turn"},"total_usd":0.088504,"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\": 2009,\n      \"finding\": \"RAB11a (PF3D7_1320600) is required for the final step of apicomplexan cytokinesis: delivery of new plasma membrane to daughter cells. Functional RAB11a was found in association with Myosin-Tail-Interacting-Protein (MTIP/MLC1), a member of the glideosome motor complex. Ablation of RAB11a function resulted in daughter parasites with an incompletely formed Inner Membrane Complex (IMC), causing a block at a late stage of cell division, phenocopied by expression of a myosin A tail-only dominant-negative mutant.\",\n      \"method\": \"Dominant-negative RAB11a expression, co-immunoprecipitation with MTIP/MLC1, fluorescence microscopy of IMC assembly, genetic epistasis with myosin A tail mutant\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction (Co-IP with MTIP), dominant-negative loss-of-function with defined cellular phenotype, genetic epistasis with myosin A mutant, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19165333\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structures of PI4KIIIβ bound to Rab11a (without and with the Rab11 effector FIP3) revealed that the Rab11a–PI4KIIIβ interface is distinct from known Rab complex structures and does not involve the switch regions typically used by GTPase effectors, providing a mechanism for simultaneous recruitment of Rab11a and its effectors on PI4P-enriched membranes.\",\n      \"method\": \"X-ray crystallography of PI4KIIIβ–Rab11a binary and ternary (with FIP3) complexes; structural comparison with known Rab complex structures\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures of the complex with and without effector, defining a novel interaction interface with structural validation\",\n      \"pmids\": [\"24876499\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PfRAB11A (PF3D7_1320600) shows a distinct subcellular distribution compared to PfRab1A, as demonstrated by generation of specific antisera and immunolocalization in P. falciparum-infected erythrocytes.\",\n      \"method\": \"Generation of specific antisera; immunofluorescence/immunolocalization of PfRab11A versus PfRab1A in infected erythrocytes\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab localization using specific antisera, no functional consequence reported\",\n      \"pmids\": [\"12657463\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PfRAB11a (PF3D7_1320600) possesses intrinsic GTPase enzymatic activity, confirmed by an orthogonal enzyme assay; small-molecule fragments and the natural product arborside E were identified as weak binders to PfRAB11a by ESI-FTICR-MS screening.\",\n      \"method\": \"ESI-FTICR-MS binding assay; orthogonal GTPase enzyme activity assay; titration experiments confirming binding\",\n      \"journal\": \"Journal of biomolecular screening\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro GTPase enzyme assay confirming enzymatic activity, single lab, confirmatory rather than mechanistically novel\",\n      \"pmids\": [\"26773071\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PbRAB11A is essential for zygote-to-ookinete morphological maturation in P. berghei. Promoter-swap-mediated downregulation of PbRAB11A had no effect on gamete production, fertility, meiosis, mitosis, or establishment of IMC/apical complex polarity, but almost totally inhibited the zygote-to-ookinete transition, leaving parasites spherical and immotile. PbRAB11A loss also impaired secretion and distribution of microneme cargo, implicating RAB11A in endosome-mediated delivery of plasma membrane components.\",\n      \"method\": \"Promoter swap strategy for conditional downregulation of PbRAB11A in gametocytes/zygotes; fluorescence microscopy of IMC and apical complex; mosquito transmission assays; assessment of microneme cargo secretion/distribution\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic knockdown with multiple orthogonal phenotypic readouts (morphology, polarity markers, microneme secretion, transmission), single lab but comprehensive analysis\",\n      \"pmids\": [\"32463831\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Functional Rab11a in the host hepatocyte is critical for the ability of P. berghei liver stage parasites to induce fragmentation of the host cell Golgi into miniaturized stacks, a process that increases surface interactions with the parasitophorous vacuolar membrane. Expression of dominant-negative Rab11a (among other dominant-negative Rab GTPases) resulted in developmental delay and diminished survival of liver stage parasites.\",\n      \"method\": \"Dominant-negative Rab GTPase expression in host hepatocytes; dynamic fluorescence-based live imaging of Golgi fragmentation; parasite developmental assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — dominant-negative expression with live-imaging phenotype, but the Rab11a tested here is the host cell (hepatocyte) Rab11a, not the parasite's own RAB11a; attribution is to parasite-induced manipulation of host Rab11a\",\n      \"pmids\": [\"34013963\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In P. yoelii ookinetes, RAB11A interacts with dynein heavy chain 3 (DHC3) at subpellicular microtubules (SPMTs) in a DHC3-dependent manner, functioning as a receptor/cargo label for SPMT-dynein-driven transport. Disruption of RAB11A phenocopied DHC3 deficiency, impairing ookinete morphogenesis, apical organelle formation/localization, and mosquito infectivity.\",\n      \"method\": \"Co-immunoprecipitation of RAB11A with DHC3; genetic disruption of RAB11A; fluorescence microscopy of ookinete morphogenesis and apical organelles; mosquito infection assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction with DHC3, genetic knockout with defined cellular phenotype, epistasis with DHC3 disruption, single lab\",\n      \"pmids\": [\"39366980\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"RAB11a (PF3D7_1320600) is a small GTPase that mediates vesicular trafficking of plasma membrane and microneme cargo during parasite cell division and morphogenesis: it physically associates with the glideosome component MTIP/MLC1 and with dynein heavy chain DHC3 at subpellicular microtubules, is required for IMC maturation and daughter cell budding during asexual replication, drives ookinete morphological maturation (including microneme secretion) in mosquito stages, and structurally engages PI4KIIIβ through a switch-region-independent interface that enables simultaneous recruitment of Rab11a and its effectors on PI4P-enriched membranes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB11a (PF3D7_1320600) is a small GTPase with confirmed intrinsic GTPase activity [#3] that governs membrane and cargo trafficking during Plasmodium cell division and morphogenesis [#0, #4]. In P. falciparum asexual blood stages it executes the final step of cytokinesis by delivering new plasma membrane to nascent daughter parasites: functional RAB11a associates with the glideosome motor component MTIP/MLC1, and its loss produces daughter cells with an incompletely formed Inner Membrane Complex, phenocopied by a myosin A tail dominant-negative mutant [#0]. In mosquito stages, RAB11a orthologs drive morphological maturation: in P. berghei it is essential for the zygote-to-ookinete transition and for secretion and distribution of microneme cargo, without affecting fertility, meiosis, mitosis, or apical/IMC polarity establishment [#4], and in P. yoelii ookinetes it acts as a cargo receptor for subpellicular-microtubule dynein-driven transport through a DHC3-dependent interaction, with its disruption impairing ookinete morphogenesis and apical organelle formation [#6]. Structurally, Rab11a engages PI4KIIIβ through an interface distinct from the switch regions normally used by GTPase effectors, permitting simultaneous recruitment of Rab11a and its effectors such as FIP3 on PI4P-enriched membranes [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that PfRAB11A occupies a subcellular compartment distinct from other parasite Rab GTPases was the first step toward assigning it a dedicated trafficking role.\",\n      \"evidence\": \"Specific antisera and immunolocalization comparing PfRab11A versus PfRab1A in infected erythrocytes\",\n      \"pmids\": [\"12657463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the localization was tested\", \"Does not identify the trafficking pathway or cargo\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The question of what completes apicomplexan cytokinesis was answered by placing RAB11a at the final membrane-delivery step, linking vesicular trafficking to the glideosome motor machinery.\",\n      \"evidence\": \"Dominant-negative RAB11a expression, Co-IP with MTIP/MLC1, IMC imaging, and genetic epistasis with a myosin A tail mutant\",\n      \"pmids\": [\"19165333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct membrane cargo carried by RAB11a not molecularly defined\", \"Nature of the RAB11a–MTIP association (direct vs. indirect) not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"How Rab11a can bind an effector kinase and its downstream effectors at once was answered structurally, revealing a switch-region-independent interface with PI4KIIIβ.\",\n      \"evidence\": \"X-ray crystallography of PI4KIIIβ–Rab11a binary and PI4KIIIβ–Rab11a–FIP3 ternary complexes\",\n      \"pmids\": [\"24876499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of this interface to parasite trafficking not demonstrated\", \"Whether the PI4KIIIβ interaction operates in the same pathway as MTIP-linked cytokinesis is untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether PfRAB11a is a bona fide enzyme was confirmed by direct demonstration of intrinsic GTPase activity, and initial chemical-probe binders were identified.\",\n      \"evidence\": \"ESI-FTICR-MS fragment screening plus an orthogonal GTPase enzyme activity assay\",\n      \"pmids\": [\"26773071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identified binders are weak with no demonstrated inhibitory or cellular effect\", \"GDP/GTP cycling regulators (GEF/GAP) not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The role of RAB11A in mosquito stages was defined by showing it is required specifically for zygote-to-ookinete morphogenesis and microneme cargo delivery rather than for the preceding sexual/mitotic events.\",\n      \"evidence\": \"Promoter-swap conditional downregulation of PbRAB11A with morphology, polarity-marker, microneme-secretion, and transmission readouts\",\n      \"pmids\": [\"32463831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the delivered plasma membrane/microneme cargo not defined\", \"Effector or motor partner in ookinetes not identified in this study\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"This study concerns host hepatocyte Rab11a co-opted by the parasite, not parasite RAB11a, establishing that parasite-induced host Golgi fragmentation and liver-stage development depend on host Rab11a function.\",\n      \"evidence\": \"Dominant-negative Rab GTPase expression in host hepatocytes with live imaging of Golgi fragmentation and parasite developmental assays\",\n      \"pmids\": [\"34013963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Attribution is to host-cell Rab11a, not the parasite's PF3D7_1320600\", \"Does not establish a role for parasite RAB11a in the liver stage\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"How RAB11A links cargo to the cytoskeletal transport machinery in ookinetes was answered by identifying it as a DHC3-dependent cargo label for subpellicular-microtubule dynein-driven transport.\",\n      \"evidence\": \"Co-IP of RAB11A with DHC3, genetic disruption, ookinete morphogenesis/apical-organelle imaging, and mosquito infection assays with DHC3 epistasis\",\n      \"pmids\": [\"39366980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of the RAB11A–DHC3 interaction not structurally established\", \"How microtubule-based transport integrates with the MTIP/glideosome pathway seen in blood stages is unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular cargo carried by parasite RAB11a and the GEF/GAP and effector network that spatially controls its GTP cycling across life-cycle stages remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No RAB11a-specific membrane cargo molecularly identified\", \"No parasite GEF/GAP regulators characterized\", \"Reconciliation of glideosome-linked (blood stage) and dynein-linked (ookinete) roles unresolved\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005525\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005088\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0030430\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005874\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0045169\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0000281\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016192\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0002079\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MTIP/MLC1 (glideosome myosin tail-interacting protein) [#0]\",\n      \"PI4KIIIβ [#1]\",\n      \"FIP3 (Rab11 effector) [#1]\",\n      \"dynein heavy chain 3 / DHC3 [#6]\"\n    ],\n    \"other_free_text\": [\n      \"Required for delivery of new plasma membrane and completion of IMC assembly during daughter-cell budding in P. falciparum asexual stages [#0].\",\n      \"Essential for zygote-to-ookinete morphological maturation and microneme cargo secretion/distribution in P. berghei [#4].\",\n      \"Acts as a cargo receptor for subpellicular-microtubule dynein-driven transport in P. yoelii ookinetes [#6].\",\n      \"Engages PI4KIIIβ via an interface independent of the GTPase switch regions, enabling simultaneous effector recruitment on PI4P-enriched membranes [#1].\",\n      \"Weak small-molecule and natural-product (arborside E) binders identified by MS screening [#3].\",\n      \"Discovery #5 concerns host hepatocyte Rab11a co-opted by the parasite, not the parasite's own PF3D7_1320600.\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1320600","name":null,"product":"ras-related protein Rab-11A","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1418900","name":null,"product":"ras-related protein Rab-11A","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1421200","name":null,"product":"ras-related protein Rab-11A, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"RAB11a","evaluation":null}