{"gene":"PF3D7_1014700","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2018,"finding":"PHB2 (prohibitin 2) in P. berghei localizes to the parasite mitochondrion and, together with PHB1 and stomatin-like protein, cannot be deleted from the Plasmodium genome, suggesting essential function. A related unusual prohibitin-like protein (PHBL, distinct from PHB2) was deletable and its loss depolarized mitochondrial membrane potential, but PHB2 itself was refractory to deletion.","method":"Genetic deletion attempts (negative result for PHB2 itself), fluorescence microscopy for subcellular localization","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by imaging and failed deletion attempts in P. berghei; single lab, two complementary approaches, but PHB2-specific functional data is the negative (non-deletable) result","pmids":["29669282"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2020,"finding":"P. falciparum PHB2 interacts with PfPHB1, as shown by yeast two-hybrid analysis and homology modelling, suggesting formation of heterodimeric supercomplexes analogous to the canonical mitochondrial inner-membrane PHB complex.","method":"Yeast two-hybrid analysis, homology modelling","journal":"Indian journal of medical microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single interaction method (yeast two-hybrid); no in-parasite biochemical validation reported in this paper","pmids":["32883936"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"PfPHB2 localizes to the P. falciparum mitochondrion (branched structures) and interacts with PfPHB1 within that organelle. Expression of PfPHB2 in PHB2-null yeast complemented growth defects, stabilized mitochondrial DNA, and retained mitochondrial integrity, demonstrating functional conservation. Rocaglamide-A inhibited growth of yeast complemented with PfPHBs and inhibited P. falciparum asexual and sexual (gametocyte/oocyst) stage growth in nanomolar ranges, validating PfPHB2 as a molecular target for Roc-A.","method":"Immunofluorescence microscopy, co-immunoprecipitation (interaction with PfPHB1), yeast complementation assay (PHB2-null yeast), mitochondrial DNA stability assay, drug growth inhibition assays (3D7, R539T, RKL-9 strains)","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (localization, co-IP, functional complementation, drug assay) in a single lab; not independently replicated","pmids":["37088154"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"R539T"},{"species":"Plasmodium falciparum","strain":"RKL-9"}]},{"year":2024,"finding":"PfPHB2 is expressed on the merozoite surface/exported compartment and interacts with human erythrocyte Hsp70A1A (HspA1A) to mediate merozoite invasion. Knockdown of PfPHB2 using a glmS ribozyme in iRBCs, or siRNA-mediated depletion of Hsp70A1A in RBCs, each inhibited parasite invasion. Recombinant PfPHB2 binds to RBCs, and this binding is blocked by anti-PfPHB2 antibody or anti-Hsp70A1A monoclonal antibody.","method":"GlmS ribozyme-mediated inducible knockdown of PfPHB2, siRNA knockdown of host Hsp70A1A, recombinant protein binding assay (ELISA/RBC-binding), antibody invasion inhibition assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (genetic knockdown in parasite, siRNA in host cell, recombinant binding assay, antibody blocking) in single lab; invasion inhibition phenotype directly linked to PfPHB2–Hsp70A1A interaction","pmids":["38812541"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfPHB2 localizes to the parasite mitochondrion throughout the asexual intraerythrocytic cycle, as determined by C-terminal tagging via selection-linked integration (SLI). Inducible GlmS ribozyme-mediated knockdown of PfPHB2 alone had no significant effect on parasite growth, but under mitochondrial stress (inhibition of the AAA-protease ClpQ), PfPHB2 depletion caused enhanced growth inhibition, mitochondrial ROS production, loss of mitochondrial membrane potential, mitochondrial fission/fragmentation, and apoptosis-like cell death. PfPHB2 depletion also increased parasite susceptibility to the mitochondria-targeting drug proguanil, indicating a functional interaction between PfPHB2 and ClpQ protease in stabilizing mitochondrial proteins.","method":"Selection-linked integration (SLI) C-terminal tagging for localization, GlmS ribozyme-mediated inducible knockdown, ROS measurement, mitochondrial membrane potential assay, mitochondrial morphology imaging, proguanil drug susceptibility assay","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by endogenous tagging, inducible knockdown with multiple functional readouts; single lab, multiple orthogonal phenotypic assays","pmids":["39245193"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"PHB2 on reticulocyte/erythrocyte membranes is a binding partner of the P. vivax invasion ligand PvRBP1a (residues 158–650), identified by TurboID proximity labeling and confirmed by ELISA binding assay, implicating PHB2 as a host co-receptor for P. vivax merozoite invasion.","method":"TurboID proximity labeling with recombinant PvRBP1a-TurboID fusion protein, ELISA binding assay, quantitative LC-MS membrane proteomics","journal":"Frontiers in cellular and infection microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling and ELISA from a single lab; PHB2 role as co-receptor is novel and not yet independently validated; the finding pertains to the host-cell PHB2 protein as a receptor for P. vivax, not to PfPHB2 itself","pmids":["41078366"],"is_preprint":false,"attribution":[{"species":"Plasmodium vivax","strain":""}]}],"current_model":"PF3D7_1014700 (PHB2) is a mitochondrially localized inner-membrane protein in P. falciparum that forms a heterodimeric complex with PHB1, maintains mitochondrial DNA stability and membrane potential, and plays an anti-apoptotic role under mitochondrial stress (functionally linked to the AAA-protease ClpQ); additionally, PfPHB2 is exposed on the merozoite surface where it interacts with host erythrocyte Hsp70A1A to facilitate invasion, and the orthologous protein on host reticulocytes serves as a receptor for the P. vivax ligand PvRBP1a."},"narrative":{"mechanistic_narrative":"PF3D7_1014700 (PHB2) is an essential mitochondrial prohibitin of Plasmodium that maintains organellar integrity while also serving a moonlighting role at the host-parasite interface during invasion [PMID:37088154, PMID:39245193]. In the parasite mitochondrion it partners with PfPHB1 to form a heterodimeric inner-membrane complex; expression of PfPHB2 complements PHB2-null yeast, restoring growth, stabilizing mitochondrial DNA, and preserving mitochondrial integrity, demonstrating conserved function [PMID:32883936, PMID:37088154]. Endogenous tagging places PfPHB2 in the branched mitochondrion throughout the asexual cycle, and although its inducible knockdown alone is tolerated, depletion under mitochondrial stress (ClpQ AAA-protease inhibition) triggers ROS accumulation, loss of membrane potential, mitochondrial fragmentation, and apoptosis-like death, and sensitizes parasites to proguanil — defining an anti-apoptotic, stress-protective role [PMID:39245193]. In P. berghei the gene is refractory to deletion, consistent with essentiality [PMID:29669282], and PfPHB2 is a nanomolar target of the anti-plasmodial compound rocaglamide-A [PMID:37088154]. Separately, PfPHB2 is displayed on the merozoite surface, where it binds host erythrocyte Hsp70A1A to drive invasion, with knockdown of either partner blocking entry [PMID:38812541]; the orthologous host reticulocyte PHB2 is also implicated as a co-receptor for the P. vivax ligand PvRBP1a [PMID:41078366].","teleology":[{"year":2018,"claim":"Establishing whether PHB2 is dispensable defined it as an essential mitochondrial factor, distinguishing it from the deletable prohibitin-like PHBL.","evidence":"Genetic deletion attempts and fluorescence localization in P. berghei","pmids":["29669282"],"confidence":"Medium","gaps":["Essentiality inferred from failed deletion, not a conditional knockout","No molecular function assigned to PHB2 in this study","PHB2-specific phenotype is a negative (non-deletable) result"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2020,"claim":"Identifying the PfPHB2-PfPHB1 interaction proposed that Plasmodium builds a canonical prohibitin heterodimeric complex analogous to the mitochondrial inner-membrane assembly.","evidence":"Yeast two-hybrid and homology modelling in P. falciparum","pmids":["32883936"],"confidence":"Low","gaps":["Single interaction method (yeast two-hybrid) without in-parasite biochemical validation","Supercomplex stoichiometry and architecture not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Functional complementation in yeast and drug-target validation demonstrated PfPHB2 is a conserved mitochondrial prohibitin maintaining mtDNA and a target of rocaglamide-A.","evidence":"Immunofluorescence, co-IP with PfPHB1, PHB2-null yeast complementation, mtDNA stability assay, and Roc-A growth inhibition across 3D7/R539T/RKL-9 strains","pmids":["37088154"],"confidence":"Medium","gaps":["Complementation shown in yeast rather than direct in-parasite loss-of-function","Roc-A binding mode to PfPHB2 not structurally defined","Not independently replicated"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"R539T"},{"species":"Plasmodium falciparum","strain":"RKL-9"}]},{"year":2024,"claim":"Conditional depletion under mitochondrial stress revealed PfPHB2's anti-apoptotic role and functional coupling to the ClpQ protease, explaining why loss becomes lethal only when protein-quality-control is compromised.","evidence":"SLI C-terminal tagging, GlmS inducible knockdown with ROS, membrane potential, morphology, and proguanil susceptibility readouts in P. falciparum","pmids":["39245193"],"confidence":"Medium","gaps":["Direct physical interaction between PfPHB2 and ClpQ not demonstrated","Substrates stabilized by the PHB2-ClpQ axis unidentified","Single lab, not independently replicated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Detection of surface-exposed PfPHB2 binding host Hsp70A1A assigned a moonlighting invasion function beyond its mitochondrial role.","evidence":"GlmS knockdown of PfPHB2, siRNA depletion of host Hsp70A1A, recombinant RBC-binding, and antibody invasion-inhibition assays","pmids":["38812541"],"confidence":"Medium","gaps":["Mechanism of PfPHB2 export/surface display from a mitochondrial protein unexplained","Downstream invasion signaling not characterized","Single lab, not independently replicated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Proximity labeling implicated host reticulocyte PHB2 as a co-receptor for the P. vivax ligand PvRBP1a, extending prohibitin's invasion relevance to the host side.","evidence":"TurboID proximity labeling with PvRBP1a-TurboID fusion, LC-MS membrane proteomics, and ELISA binding","pmids":["41078366"],"confidence":"Low","gaps":["Concerns host-cell PHB2, not the parasite PF3D7_1014700 protein","Co-receptor role novel and not independently validated","Functional invasion requirement not tested by loss-of-function"],"attribution":[{"species":"Plasmodium vivax","strain":""}]},{"year":null,"claim":"How a mitochondrial prohibitin reaches the merozoite surface, and whether the PfPHB2-ClpQ and PfPHB2-Hsp70A1A functions are mechanistically linked, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Export/trafficking route to the merozoite surface unknown","No structure of the PfPHB1-PfPHB2 complex","Direct PfPHB2-ClpQ interaction unproven"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PfPHB1-PfPHB2 mitochondrial inner-membrane prohibitin heterodimer/supercomplex [#1, #2]"],"partners":["PFPHB1 (MITOCHONDRIAL PROHIBITIN PARTNER) [#1, #2]","HUMAN ERYTHROCYTE HSP70A1A/HSPA1A (INVASION) [#3]","CLPQ AAA-PROTEASE (FUNCTIONAL INTERACTION UNDER MITOCHONDRIAL STRESS) [#4]","P. VIVAX PVRBP1A (HOST PHB2 AS CO-RECEPTOR) [#5]"],"other_free_text":["Essential/non-deletable in P. berghei [#0]","Nanomolar target of rocaglamide-A across asexual and sexual stages [#2]","Depletion increases susceptibility to proguanil [#4]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"29669282","id":"PMC_29669282","title":"An Unusual Prohibitin Regulates Malaria Parasite Mitochondrial Membrane Potential.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29669282","citation_count":28,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["prohibitin 2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37088154","id":"PMC_37088154","title":"Characterization of Plasmodium falciparum prohibitins as novel targets to block infection in humans by impairing the growth and transmission of the parasite.","date":"2023","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37088154","citation_count":9,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PHB2","PfPHB2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32883936","id":"PMC_32883936","title":"Functional studies of Plasmodium falciparum's prohibitin1 and prohibitin 2 in yeast.","date":"2020","source":"Indian journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32883936","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PHB2","prohibitin 2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38812541","id":"PMC_38812541","title":"Targeting PfProhibitin 2-Hu-Hsp70A1A complex as a unique approach towards malaria vaccine development.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38812541","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfPHB2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39245193","id":"PMC_39245193","title":"Unravelling the anti-apoptotic role of Plasmodium falciparum Prohibitin-2 (PfPhb2) in maintaining mitochondrial homeostasis.","date":"2024","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/39245193","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["prohibitin 2","PfPHB2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40669099","id":"PMC_40669099","title":"Development of a multi-epitope vaccine candidate targeting blood-stage of malaria through immunoinformatics approach.","date":"2025","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40669099","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfPHB2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41078366","id":"PMC_41078366","title":"The reticulocyte restriction: invasion ligand RBP1a of Plasmodium vivax targets human TfR1, prohibitin-2, and basigin.","date":"2025","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41078366","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PHB2","prohibitin 2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6509,"output_tokens":2209,"usd":0.026331,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7477,"output_tokens":3103,"usd":0.05748,"stage2_stop_reason":"end_turn"},"total_usd":0.083811,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"PHB2 (prohibitin 2) in P. berghei localizes to the parasite mitochondrion and, together with PHB1 and stomatin-like protein, cannot be deleted from the Plasmodium genome, suggesting essential function. A related unusual prohibitin-like protein (PHBL, distinct from PHB2) was deletable and its loss depolarized mitochondrial membrane potential, but PHB2 itself was refractory to deletion.\",\n      \"method\": \"Genetic deletion attempts (negative result for PHB2 itself), fluorescence microscopy for subcellular localization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by imaging and failed deletion attempts in P. berghei; single lab, two complementary approaches, but PHB2-specific functional data is the negative (non-deletable) result\",\n      \"pmids\": [\"29669282\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"P. falciparum PHB2 interacts with PfPHB1, as shown by yeast two-hybrid analysis and homology modelling, suggesting formation of heterodimeric supercomplexes analogous to the canonical mitochondrial inner-membrane PHB complex.\",\n      \"method\": \"Yeast two-hybrid analysis, homology modelling\",\n      \"journal\": \"Indian journal of medical microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single interaction method (yeast two-hybrid); no in-parasite biochemical validation reported in this paper\",\n      \"pmids\": [\"32883936\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PfPHB2 localizes to the P. falciparum mitochondrion (branched structures) and interacts with PfPHB1 within that organelle. Expression of PfPHB2 in PHB2-null yeast complemented growth defects, stabilized mitochondrial DNA, and retained mitochondrial integrity, demonstrating functional conservation. Rocaglamide-A inhibited growth of yeast complemented with PfPHBs and inhibited P. falciparum asexual and sexual (gametocyte/oocyst) stage growth in nanomolar ranges, validating PfPHB2 as a molecular target for Roc-A.\",\n      \"method\": \"Immunofluorescence microscopy, co-immunoprecipitation (interaction with PfPHB1), yeast complementation assay (PHB2-null yeast), mitochondrial DNA stability assay, drug growth inhibition assays (3D7, R539T, RKL-9 strains)\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (localization, co-IP, functional complementation, drug assay) in a single lab; not independently replicated\",\n      \"pmids\": [\"37088154\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"R539T\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"RKL-9\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfPHB2 is expressed on the merozoite surface/exported compartment and interacts with human erythrocyte Hsp70A1A (HspA1A) to mediate merozoite invasion. Knockdown of PfPHB2 using a glmS ribozyme in iRBCs, or siRNA-mediated depletion of Hsp70A1A in RBCs, each inhibited parasite invasion. Recombinant PfPHB2 binds to RBCs, and this binding is blocked by anti-PfPHB2 antibody or anti-Hsp70A1A monoclonal antibody.\",\n      \"method\": \"GlmS ribozyme-mediated inducible knockdown of PfPHB2, siRNA knockdown of host Hsp70A1A, recombinant protein binding assay (ELISA/RBC-binding), antibody invasion inhibition assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (genetic knockdown in parasite, siRNA in host cell, recombinant binding assay, antibody blocking) in single lab; invasion inhibition phenotype directly linked to PfPHB2–Hsp70A1A interaction\",\n      \"pmids\": [\"38812541\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfPHB2 localizes to the parasite mitochondrion throughout the asexual intraerythrocytic cycle, as determined by C-terminal tagging via selection-linked integration (SLI). Inducible GlmS ribozyme-mediated knockdown of PfPHB2 alone had no significant effect on parasite growth, but under mitochondrial stress (inhibition of the AAA-protease ClpQ), PfPHB2 depletion caused enhanced growth inhibition, mitochondrial ROS production, loss of mitochondrial membrane potential, mitochondrial fission/fragmentation, and apoptosis-like cell death. PfPHB2 depletion also increased parasite susceptibility to the mitochondria-targeting drug proguanil, indicating a functional interaction between PfPHB2 and ClpQ protease in stabilizing mitochondrial proteins.\",\n      \"method\": \"Selection-linked integration (SLI) C-terminal tagging for localization, GlmS ribozyme-mediated inducible knockdown, ROS measurement, mitochondrial membrane potential assay, mitochondrial morphology imaging, proguanil drug susceptibility assay\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by endogenous tagging, inducible knockdown with multiple functional readouts; single lab, multiple orthogonal phenotypic assays\",\n      \"pmids\": [\"39245193\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PHB2 on reticulocyte/erythrocyte membranes is a binding partner of the P. vivax invasion ligand PvRBP1a (residues 158–650), identified by TurboID proximity labeling and confirmed by ELISA binding assay, implicating PHB2 as a host co-receptor for P. vivax merozoite invasion.\",\n      \"method\": \"TurboID proximity labeling with recombinant PvRBP1a-TurboID fusion protein, ELISA binding assay, quantitative LC-MS membrane proteomics\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling and ELISA from a single lab; PHB2 role as co-receptor is novel and not yet independently validated; the finding pertains to the host-cell PHB2 protein as a receptor for P. vivax, not to PfPHB2 itself\",\n      \"pmids\": [\"41078366\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1014700 (PHB2) is a mitochondrially localized inner-membrane protein in P. falciparum that forms a heterodimeric complex with PHB1, maintains mitochondrial DNA stability and membrane potential, and plays an anti-apoptotic role under mitochondrial stress (functionally linked to the AAA-protease ClpQ); additionally, PfPHB2 is exposed on the merozoite surface where it interacts with host erythrocyte Hsp70A1A to facilitate invasion, and the orthologous protein on host reticulocytes serves as a receptor for the P. vivax ligand PvRBP1a.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1014700 (PHB2) is an essential mitochondrial prohibitin of Plasmodium that maintains organellar integrity while also serving a moonlighting role at the host-parasite interface during invasion [#2, #4]. In the parasite mitochondrion it partners with PfPHB1 to form a heterodimeric inner-membrane complex; expression of PfPHB2 complements PHB2-null yeast, restoring growth, stabilizing mitochondrial DNA, and preserving mitochondrial integrity, demonstrating conserved function [#1, #2]. Endogenous tagging places PfPHB2 in the branched mitochondrion throughout the asexual cycle, and although its inducible knockdown alone is tolerated, depletion under mitochondrial stress (ClpQ AAA-protease inhibition) triggers ROS accumulation, loss of membrane potential, mitochondrial fragmentation, and apoptosis-like death, and sensitizes parasites to proguanil — defining an anti-apoptotic, stress-protective role [#4]. In P. berghei the gene is refractory to deletion, consistent with essentiality [#0], and PfPHB2 is a nanomolar target of the anti-plasmodial compound rocaglamide-A [#2]. Separately, PfPHB2 is displayed on the merozoite surface, where it binds host erythrocyte Hsp70A1A to drive invasion, with knockdown of either partner blocking entry [#3]; the orthologous host reticulocyte PHB2 is also implicated as a co-receptor for the P. vivax ligand PvRBP1a [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing whether PHB2 is dispensable defined it as an essential mitochondrial factor, distinguishing it from the deletable prohibitin-like PHBL.\",\n      \"evidence\": \"Genetic deletion attempts and fluorescence localization in P. berghei\",\n      \"pmids\": [\"29669282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Essentiality inferred from failed deletion, not a conditional knockout\", \"No molecular function assigned to PHB2 in this study\", \"PHB2-specific phenotype is a negative (non-deletable) result\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying the PfPHB2-PfPHB1 interaction proposed that Plasmodium builds a canonical prohibitin heterodimeric complex analogous to the mitochondrial inner-membrane assembly.\",\n      \"evidence\": \"Yeast two-hybrid and homology modelling in P. falciparum\",\n      \"pmids\": [\"32883936\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single interaction method (yeast two-hybrid) without in-parasite biochemical validation\", \"Supercomplex stoichiometry and architecture not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional complementation in yeast and drug-target validation demonstrated PfPHB2 is a conserved mitochondrial prohibitin maintaining mtDNA and a target of rocaglamide-A.\",\n      \"evidence\": \"Immunofluorescence, co-IP with PfPHB1, PHB2-null yeast complementation, mtDNA stability assay, and Roc-A growth inhibition across 3D7/R539T/RKL-9 strains\",\n      \"pmids\": [\"37088154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Complementation shown in yeast rather than direct in-parasite loss-of-function\", \"Roc-A binding mode to PfPHB2 not structurally defined\", \"Not independently replicated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"R539T\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"RKL-9\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional depletion under mitochondrial stress revealed PfPHB2's anti-apoptotic role and functional coupling to the ClpQ protease, explaining why loss becomes lethal only when protein-quality-control is compromised.\",\n      \"evidence\": \"SLI C-terminal tagging, GlmS inducible knockdown with ROS, membrane potential, morphology, and proguanil susceptibility readouts in P. falciparum\",\n      \"pmids\": [\"39245193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between PfPHB2 and ClpQ not demonstrated\", \"Substrates stabilized by the PHB2-ClpQ axis unidentified\", \"Single lab, not independently replicated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Detection of surface-exposed PfPHB2 binding host Hsp70A1A assigned a moonlighting invasion function beyond its mitochondrial role.\",\n      \"evidence\": \"GlmS knockdown of PfPHB2, siRNA depletion of host Hsp70A1A, recombinant RBC-binding, and antibody invasion-inhibition assays\",\n      \"pmids\": [\"38812541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PfPHB2 export/surface display from a mitochondrial protein unexplained\", \"Downstream invasion signaling not characterized\", \"Single lab, not independently replicated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proximity labeling implicated host reticulocyte PHB2 as a co-receptor for the P. vivax ligand PvRBP1a, extending prohibitin's invasion relevance to the host side.\",\n      \"evidence\": \"TurboID proximity labeling with PvRBP1a-TurboID fusion, LC-MS membrane proteomics, and ELISA binding\",\n      \"pmids\": [\"41078366\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Concerns host-cell PHB2, not the parasite PF3D7_1014700 protein\", \"Co-receptor role novel and not independently validated\", \"Functional invasion requirement not tested by loss-of-function\"],\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a mitochondrial prohibitin reaches the merozoite surface, and whether the PfPHB2-ClpQ and PfPHB2-Hsp70A1A functions are mechanistically linked, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Export/trafficking route to the merozoite surface unknown\", \"No structure of the PfPHB1-PfPHB2 complex\", \"Direct PfPHB2-ClpQ interaction unproven\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042803\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0030674\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007005\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0043066\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\n      \"PfPHB1-PfPHB2 mitochondrial inner-membrane prohibitin heterodimer/supercomplex [#1, #2]\"\n    ],\n    \"partners\": [\n      \"PfPHB1 (mitochondrial prohibitin partner) [#1, #2]\",\n      \"Human erythrocyte Hsp70A1A/HspA1A (invasion) [#3]\",\n      \"ClpQ AAA-protease (functional interaction under mitochondrial stress) [#4]\",\n      \"P. vivax PvRBP1a (host PHB2 as co-receptor) [#5]\"\n    ],\n    \"other_free_text\": [\n      \"Essential/non-deletable in P. berghei [#0]\",\n      \"Nanomolar target of rocaglamide-A across asexual and sexual stages [#2]\",\n      \"Depletion increases susceptibility to proguanil [#4]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1014700","name":null,"product":"prohibitin 2","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1213100","name":null,"product":"prohibitin 2","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0814800","name":null,"product":"prohibitin 2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PHB2","evaluation":null}