{"gene":"PF3D7_1251200","run_date":"2026-09-08T16:55:36+00:00","timeline":{"discoveries":[{"year":1998,"finding":"PfCoronin (PF3D7_1251200) is a single-copy gene encoding a 42-kDa protein with WD repeats homologous to Dictyostelium coronin; the recombinant protein co-sediments with exogenous F-actin and is found in the Triton-insoluble fraction containing parasite actin filaments, demonstrating direct F-actin binding.","method":"Affinity-purified monoclonal antibody cross-reactivity, co-sedimentation assay with exogenous F-actin, Triton fractionation of P. falciparum schizont extracts","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — direct in vitro co-sedimentation assay establishing F-actin binding, single lab, single study","pmids":["9883894"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"The N-terminal β-propeller domain of PfCoronin binds pre-formed F-actin and facilitates formation of parallel actin filament bundles; PfCoronin localizes to the pellicle region of invasive merozoites before and during erythrocyte entry and associates with membranes, likely via interaction with PI(4,5)P2.","method":"Recombinant protein expression, F-actin sedimentation assay, TIRF microscopy, confocal imaging, phospholipid-binding assay, tagged PfCoronin parasite line generation and live/fixed imaging","journal":"Malaria journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical and cell-biological methods (sedimentation, TIRF, confocal, lipid binding, tagged parasite line) in a single rigorous study","pmids":["26187846"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"Coronin regulates gliding motility in P. berghei sporozoites; parasites lacking coronin show motility defects that impair salivary gland colonization but not skin migration, reducing transmission efficiency. In non-motile sporozoites, low calcium mediates actin-independent coronin localization to the periphery; calcium release triggers actin-dependent relocalization of coronin to the rear and motility initiation. Protein kinase A contributes to actin filament disassembly downstream of coronin.","method":"Genetic knockout of coronin in P. berghei, live imaging, mutational analysis, calcium signaling perturbation, cAMP/PKA pharmacological manipulation","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with defined motility phenotype, live imaging, mutational analysis, and signaling pathway dissection in a single study","pmids":["27409081"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2018,"finding":"Overexpression of coronin in P. berghei rescues the penetration defects caused by actin subdomain mutations, placing coronin as a functional actin filament regulator that can compensate for reduced inter-subunit actin dynamics in motile parasites.","method":"Genetic rescue experiment — coronin overexpression in actin-mutant P. berghei parasites, mosquito organ penetration assay","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic rescue with defined phenotype, single lab, single study","pmids":["30011270"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2018,"finding":"Specific mutations in PfCoronin (arising independently in two West African P. falciparum isolates under DHA selection) are sufficient to reduce artemisinin susceptibility when introduced into parental parasites by CRISPR/Cas9, establishing PfCoronin mutations as a functional determinant of ART resistance independent of PfKelch13.","method":"Long-term in vitro DHA selection, whole-genome sequencing, CRISPR/Cas9-mediated gene editing, ring-stage survival assay (RSA)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR/Cas9 allelic replacement with functional RSA readout, two independent selections converging on the same gene, single lab","pmids":["30420498"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfCoronin interacts with PfActin and localizes to the parasite plasma membrane, digestive vacuole membrane, and a newly identified preDV compartment involved in hemoglobin trafficking. Resistance-associated PfCoronin mutations disrupt PfActin homeostasis, impair preDV development and morphology, and decrease hemoglobin uptake by ring-stage parasites, identifying impaired endocytosis as the mechanism of PfCoronin-mediated ART resistance.","method":"Co-immunoprecipitation (PfCoronin–PfActin interaction), fluorescence localization (live and fixed imaging), CRISPR/Cas9 introduction of resistance mutations, hemoglobin uptake assay, preDV morphology analysis","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal protein interaction, direct localization with functional consequence, genetic mutation introduction with quantified endocytic phenotype, multiple orthogonal methods; preprint but highly detailed mechanistic study","pmids":["38187525"],"is_preprint":true,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"PfCoronin is non-essential for parasite viability but is an actin regulator active during ring stage; resistance-associated mutations disrupt PfCoronin's interaction with PfActin and its ring-stage localization, leading to impaired endocytosis and reduced hemoglobin acquisition. PfCoronin and PfKelch13 function in distinct cellular regions but converge to limit heme availability and artemisinin activation.","method":"Genetic knockout (dispensability), CRISPR/Cas9 mutation introduction, co-immunoprecipitation (PfCoronin–PfActin), localization imaging, endocytosis/hemoglobin uptake assays, epistasis with PfKelch13 pathway","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic KO establishing dispensability, allelic replacement, protein interaction assay, localization with functional consequence, pathway epistasis; multiple orthogonal methods, single lab preprint","pmids":["40964400"],"is_preprint":true,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfCoronin (PF3D7_1251200) is a WD40/β-propeller actin filament-binding protein that directly binds and bundles F-actin, localizes to the parasite plasma membrane, digestive vacuole membrane, and a preDV compartment in ring-stage parasites; it interacts with PfActin to facilitate endocytic hemoglobin uptake, and resistance-associated mutations in PfCoronin disrupt PfActin homeostasis and impair hemoglobin acquisition, thereby reducing heme-dependent artemisinin activation and conferring partial ART resistance via a pathway parallel to but distinct from PfKelch13-mediated resistance."},"narrative":{"mechanistic_narrative":"PfCoronin (PF3D7_1251200) is a WD40/β-propeller actin filament-binding protein that acts as a regulator of PfActin dynamics across the Plasmodium life cycle [PMID:9883894, PMID:26187846]. It directly binds pre-formed F-actin through its N-terminal β-propeller domain and promotes formation of parallel actin filament bundles, and it associates with membranes, likely through PI(4,5)P2 [PMID:9883894, PMID:26187846]. In P. falciparum, PfCoronin localizes to the parasite plasma membrane, the digestive vacuole membrane, and a preDV compartment implicated in hemoglobin trafficking, and it interacts with PfActin to support ring-stage endocytic hemoglobin uptake [PMID:38187525, PMID:40964400]. In P. berghei sporozoites, coronin regulates gliding motility: calcium-triggered, actin-dependent relocalization of coronin to the cell rear initiates motility, and coronin overexpression can rescue penetration defects caused by actin subdomain mutations, establishing it as a functional actin filament regulator [PMID:27409081, PMID:30011270]. PfCoronin is dispensable for parasite viability, but resistance-associated mutations disrupt its interaction with PfActin and its ring-stage localization, impairing preDV development and reducing hemoglobin acquisition; the resulting reduction in heme-dependent artemisinin activation confers partial ART resistance through a pathway parallel to but distinct from PfKelch13 [PMID:30420498, PMID:38187525, PMID:40964400].","teleology":[{"year":1998,"claim":"Establishing whether the WD-repeat coronin homolog in P. falciparum actually engages the actin cytoskeleton was the first step in assigning it a function.","evidence":"Co-sedimentation of recombinant protein with exogenous F-actin and Triton fractionation of schizont extracts","pmids":["9883894"],"confidence":"Medium","gaps":["Binding shown with exogenous, not native parasite, F-actin","No domain mapping of the actin-binding region","No cellular localization or phenotype"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"Beyond simple binding, it was unclear how PfCoronin engages actin and where it acts, so the domain requirement and subcellular context were defined.","evidence":"Recombinant β-propeller F-actin sedimentation and TIRF bundling assays, phospholipid binding, and imaging of a tagged parasite line","pmids":["26187846"],"confidence":"High","gaps":["Functional consequence of bundling in vivo not tested","PI(4,5)P2 interaction inferred, not directly proven in situ","Role limited to invasive merozoite stage in this study"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Whether coronin has a required in vivo role was addressed genetically, linking it to actin-dependent gliding motility and its signaling control.","evidence":"Genetic knockout in P. berghei with live imaging, calcium and cAMP/PKA perturbation","pmids":["27409081"],"confidence":"High","gaps":["Direct molecular link between PKA and coronin-dependent filament disassembly not defined","Findings are in P. berghei sporozoites, not P. falciparum blood stages","Mechanism of calcium-triggered relocalization unresolved"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2018,"claim":"To place coronin causally within actin regulation, whether it could compensate for defective actin dynamics was tested.","evidence":"Coronin overexpression rescue of actin subdomain-mutant P. berghei parasites in a mosquito organ penetration assay","pmids":["30011270"],"confidence":"Medium","gaps":["Molecular basis of rescue not defined","Restricted to motile mosquito stages","Does not address blood-stage function"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2018,"claim":"The clinical significance of PfCoronin emerged when it was asked whether mutations alone could reduce artemisinin susceptibility independent of PfKelch13.","evidence":"In vitro DHA selection, whole-genome sequencing, and CRISPR/Cas9 allelic replacement with ring-stage survival assay readout","pmids":["30420498"],"confidence":"High","gaps":["Mechanism connecting mutations to resistance not established","Cellular process affected unknown at this stage","Relationship to PfKelch13 pathway undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"The mechanism of PfCoronin-mediated resistance was resolved by tying the protein to PfActin, hemoglobin-trafficking compartments, and endocytosis.","evidence":"Co-immunoprecipitation of PfCoronin–PfActin, live/fixed localization, CRISPR/Cas9 introduction of resistance mutations, and hemoglobin uptake and preDV morphology assays (preprint)","pmids":["38187525"],"confidence":"High","gaps":["Preprint, not peer-reviewed","How preDV compartment couples to the digestive vacuole not fully defined","Quantitative link from reduced uptake to heme-dependent drug activation not directly measured"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"The genetic requirement and pathway relationship were formalized, showing PfCoronin is dispensable and acts in a ring-stage endocytic pathway that converges with PfKelch13 on heme availability.","evidence":"Genetic knockout for dispensability, allelic replacement, PfCoronin–PfActin co-immunoprecipitation, localization imaging, hemoglobin uptake assays, and epistasis with PfKelch13 (preprint)","pmids":["40964400"],"confidence":"High","gaps":["Preprint, not peer-reviewed","Distinct cellular regions of PfCoronin vs PfKelch13 action not spatially resolved in detail","Structural basis for mutation-driven loss of PfActin interaction unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How resistance-associated substitutions in the β-propeller structurally disrupt PfActin binding and preDV endocytosis, and how this quantitatively limits heme-dependent artemisinin activation, remains open.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of mutant PfCoronin–PfActin complex","Direct measurement of heme flux downstream of reduced hemoglobin uptake absent","Mechanistic overlap with PfKelch13 endocytosis not molecularly defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFACTIN","PFKELCH13 (FUNCTIONALLY CONVERGENT PATHWAY, NOT PHYSICAL PARTNER)"],"other_free_text":["N-terminal WD40/β-propeller domain mediates F-actin binding and bundling [#1]","Membrane association attributed to PI(4,5)P2 binding [#1]","In P. berghei sporozoites, calcium- and PKA-linked signaling controls coronin relocalization and actin filament disassembly during gliding motility [#2]","Non-essential for parasite viability; resistance-associated mutations impair PfActin homeostasis and ring-stage hemoglobin uptake, conferring partial artemisinin resistance distinct from PfKelch13 [#4, #5, #6]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"30420498","id":"PMC_30420498","title":"Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30420498","citation_count":130,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27409081","id":"PMC_27409081","title":"The Actin Filament-Binding Protein Coronin Regulates Motility in Plasmodium Sporozoites.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/27409081","citation_count":53,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9883894","id":"PMC_9883894","title":"A Plasmodium falciparum novel gene encoding a coronin-like protein which associates with actin filaments.","date":"1998","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9883894","citation_count":53,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26187846","id":"PMC_26187846","title":"Plasmodium falciparum coronin organizes arrays of parallel actin filaments potentially guiding directional motility in invasive malaria parasites.","date":"2015","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/26187846","citation_count":41,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31606696","id":"PMC_31606696","title":"Profiles of Kelch mutations in Plasmodium falciparum across South Asia and their implications for tracking drug resistance.","date":"2019","source":"International journal for parasitology. Drugs and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/31606696","citation_count":38,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30011270","id":"PMC_30011270","title":"Inter-subunit interactions drive divergent dynamics in mammalian and Plasmodium actin filaments.","date":"2018","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/30011270","citation_count":36,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33095255","id":"PMC_33095255","title":"Artemisinin susceptibility in the malaria parasite Plasmodium falciparum: propellers, adaptor proteins and the need for cellular healing.","date":"2021","source":"FEMS microbiology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/33095255","citation_count":30,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33045351","id":"PMC_33045351","title":"Absence of association between polymorphisms in the pfcoronin and pfk13 genes and the presence of Plasmodium falciparum parasites after treatment with artemisinin derivatives in Senegal.","date":"2020","source":"International journal of antimicrobial agents","url":"https://pubmed.ncbi.nlm.nih.gov/33045351","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32513171","id":"PMC_32513171","title":"Surveillance of genetic markers associated with Plasmodium falciparum resistance to artemisinin-based combination therapy in Pakistan, 2018-2019.","date":"2020","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/32513171","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38716192","id":"PMC_38716192","title":"Detection of novel Plasmodium falciparum coronin gene mutations in a recrudescent ACT-treated patient in South-Western Nigeria.","date":"2024","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38716192","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37702516","id":"PMC_37702516","title":"Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses.","date":"2023","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/37702516","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38187525","id":"PMC_38187525","title":"Artemisinin resistance mutations in Pfcoronin impede hemoglobin uptake.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38187525","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38456076","id":"PMC_38456076","title":"Putative molecular markers of Plasmodium falciparum resistance to antimalarial drugs in malaria parasites from Ghana.","date":"2024","source":"Frontiers in epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/38456076","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40964400","id":"PMC_40964400","title":"Cellular and molecular basis of Pf Coronin function in artemisinin resistance in Plasmodium falciparum.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40964400","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36711954","id":"PMC_36711954","title":"Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711954","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27482908","id":"PMC_27482908","title":"Correction: The Actin Filament-Binding Protein Coronin Regulates Motility in Plasmodium Sporozoites.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/27482908","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["coronin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11826,"output_tokens":2183,"usd":0.034112,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7438,"output_tokens":3373,"usd":0.060757,"stage2_stop_reason":"end_turn"},"total_usd":0.0,"stage1_batch_id":"msgbatch_01FCDwJBogPrvFL5RpW1bgoz","stage2_batch_id":"msgbatch_017MJf5R7pwT6SSC5ZnYgqis","note":"batch pricing = 50% of standard","skipped":true},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"PfCoronin (PF3D7_1251200) is a single-copy gene encoding a 42-kDa protein with WD repeats homologous to Dictyostelium coronin; the recombinant protein co-sediments with exogenous F-actin and is found in the Triton-insoluble fraction containing parasite actin filaments, demonstrating direct F-actin binding.\",\n      \"method\": \"Affinity-purified monoclonal antibody cross-reactivity, co-sedimentation assay with exogenous F-actin, Triton fractionation of P. falciparum schizont extracts\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — direct in vitro co-sedimentation assay establishing F-actin binding, single lab, single study\",\n      \"pmids\": [\"9883894\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The N-terminal β-propeller domain of PfCoronin binds pre-formed F-actin and facilitates formation of parallel actin filament bundles; PfCoronin localizes to the pellicle region of invasive merozoites before and during erythrocyte entry and associates with membranes, likely via interaction with PI(4,5)P2.\",\n      \"method\": \"Recombinant protein expression, F-actin sedimentation assay, TIRF microscopy, confocal imaging, phospholipid-binding assay, tagged PfCoronin parasite line generation and live/fixed imaging\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical and cell-biological methods (sedimentation, TIRF, confocal, lipid binding, tagged parasite line) in a single rigorous study\",\n      \"pmids\": [\"26187846\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Coronin regulates gliding motility in P. berghei sporozoites; parasites lacking coronin show motility defects that impair salivary gland colonization but not skin migration, reducing transmission efficiency. In non-motile sporozoites, low calcium mediates actin-independent coronin localization to the periphery; calcium release triggers actin-dependent relocalization of coronin to the rear and motility initiation. Protein kinase A contributes to actin filament disassembly downstream of coronin.\",\n      \"method\": \"Genetic knockout of coronin in P. berghei, live imaging, mutational analysis, calcium signaling perturbation, cAMP/PKA pharmacological manipulation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with defined motility phenotype, live imaging, mutational analysis, and signaling pathway dissection in a single study\",\n      \"pmids\": [\"27409081\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Overexpression of coronin in P. berghei rescues the penetration defects caused by actin subdomain mutations, placing coronin as a functional actin filament regulator that can compensate for reduced inter-subunit actin dynamics in motile parasites.\",\n      \"method\": \"Genetic rescue experiment — coronin overexpression in actin-mutant P. berghei parasites, mosquito organ penetration assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic rescue with defined phenotype, single lab, single study\",\n      \"pmids\": [\"30011270\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Specific mutations in PfCoronin (arising independently in two West African P. falciparum isolates under DHA selection) are sufficient to reduce artemisinin susceptibility when introduced into parental parasites by CRISPR/Cas9, establishing PfCoronin mutations as a functional determinant of ART resistance independent of PfKelch13.\",\n      \"method\": \"Long-term in vitro DHA selection, whole-genome sequencing, CRISPR/Cas9-mediated gene editing, ring-stage survival assay (RSA)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR/Cas9 allelic replacement with functional RSA readout, two independent selections converging on the same gene, single lab\",\n      \"pmids\": [\"30420498\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfCoronin interacts with PfActin and localizes to the parasite plasma membrane, digestive vacuole membrane, and a newly identified preDV compartment involved in hemoglobin trafficking. Resistance-associated PfCoronin mutations disrupt PfActin homeostasis, impair preDV development and morphology, and decrease hemoglobin uptake by ring-stage parasites, identifying impaired endocytosis as the mechanism of PfCoronin-mediated ART resistance.\",\n      \"method\": \"Co-immunoprecipitation (PfCoronin–PfActin interaction), fluorescence localization (live and fixed imaging), CRISPR/Cas9 introduction of resistance mutations, hemoglobin uptake assay, preDV morphology analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal protein interaction, direct localization with functional consequence, genetic mutation introduction with quantified endocytic phenotype, multiple orthogonal methods; preprint but highly detailed mechanistic study\",\n      \"pmids\": [\"38187525\"],\n      \"is_preprint\": true,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PfCoronin is non-essential for parasite viability but is an actin regulator active during ring stage; resistance-associated mutations disrupt PfCoronin's interaction with PfActin and its ring-stage localization, leading to impaired endocytosis and reduced hemoglobin acquisition. PfCoronin and PfKelch13 function in distinct cellular regions but converge to limit heme availability and artemisinin activation.\",\n      \"method\": \"Genetic knockout (dispensability), CRISPR/Cas9 mutation introduction, co-immunoprecipitation (PfCoronin–PfActin), localization imaging, endocytosis/hemoglobin uptake assays, epistasis with PfKelch13 pathway\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic KO establishing dispensability, allelic replacement, protein interaction assay, localization with functional consequence, pathway epistasis; multiple orthogonal methods, single lab preprint\",\n      \"pmids\": [\"40964400\"],\n      \"is_preprint\": true,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfCoronin (PF3D7_1251200) is a WD40/β-propeller actin filament-binding protein that directly binds and bundles F-actin, localizes to the parasite plasma membrane, digestive vacuole membrane, and a preDV compartment in ring-stage parasites; it interacts with PfActin to facilitate endocytic hemoglobin uptake, and resistance-associated mutations in PfCoronin disrupt PfActin homeostasis and impair hemoglobin acquisition, thereby reducing heme-dependent artemisinin activation and conferring partial ART resistance via a pathway parallel to but distinct from PfKelch13-mediated resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PfCoronin (PF3D7_1251200) is a WD40/\\u03b2-propeller actin filament-binding protein that acts as a regulator of PfActin dynamics across the Plasmodium life cycle [#0, #1]. It directly binds pre-formed F-actin through its N-terminal \\u03b2-propeller domain and promotes formation of parallel actin filament bundles, and it associates with membranes, likely through PI(4,5)P2 [#0, #1]. In P. falciparum, PfCoronin localizes to the parasite plasma membrane, the digestive vacuole membrane, and a preDV compartment implicated in hemoglobin trafficking, and it interacts with PfActin to support ring-stage endocytic hemoglobin uptake [#5, #6]. In P. berghei sporozoites, coronin regulates gliding motility: calcium-triggered, actin-dependent relocalization of coronin to the cell rear initiates motility, and coronin overexpression can rescue penetration defects caused by actin subdomain mutations, establishing it as a functional actin filament regulator [#2, #3]. PfCoronin is dispensable for parasite viability, but resistance-associated mutations disrupt its interaction with PfActin and its ring-stage localization, impairing preDV development and reducing hemoglobin acquisition; the resulting reduction in heme-dependent artemisinin activation confers partial ART resistance through a pathway parallel to but distinct from PfKelch13 [#4, #5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing whether the WD-repeat coronin homolog in P. falciparum actually engages the actin cytoskeleton was the first step in assigning it a function.\",\n      \"evidence\": \"Co-sedimentation of recombinant protein with exogenous F-actin and Triton fractionation of schizont extracts\",\n      \"pmids\": [\"9883894\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Binding shown with exogenous, not native parasite, F-actin\", \"No domain mapping of the actin-binding region\", \"No cellular localization or phenotype\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Beyond simple binding, it was unclear how PfCoronin engages actin and where it acts, so the domain requirement and subcellular context were defined.\",\n      \"evidence\": \"Recombinant \\u03b2-propeller F-actin sedimentation and TIRF bundling assays, phospholipid binding, and imaging of a tagged parasite line\",\n      \"pmids\": [\"26187846\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of bundling in vivo not tested\", \"PI(4,5)P2 interaction inferred, not directly proven in situ\", \"Role limited to invasive merozoite stage in this study\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether coronin has a required in vivo role was addressed genetically, linking it to actin-dependent gliding motility and its signaling control.\",\n      \"evidence\": \"Genetic knockout in P. berghei with live imaging, calcium and cAMP/PKA perturbation\",\n      \"pmids\": [\"27409081\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular link between PKA and coronin-dependent filament disassembly not defined\", \"Findings are in P. berghei sporozoites, not P. falciparum blood stages\", \"Mechanism of calcium-triggered relocalization unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"To place coronin causally within actin regulation, whether it could compensate for defective actin dynamics was tested.\",\n      \"evidence\": \"Coronin overexpression rescue of actin subdomain-mutant P. berghei parasites in a mosquito organ penetration assay\",\n      \"pmids\": [\"30011270\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis of rescue not defined\", \"Restricted to motile mosquito stages\", \"Does not address blood-stage function\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The clinical significance of PfCoronin emerged when it was asked whether mutations alone could reduce artemisinin susceptibility independent of PfKelch13.\",\n      \"evidence\": \"In vitro DHA selection, whole-genome sequencing, and CRISPR/Cas9 allelic replacement with ring-stage survival assay readout\",\n      \"pmids\": [\"30420498\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism connecting mutations to resistance not established\", \"Cellular process affected unknown at this stage\", \"Relationship to PfKelch13 pathway undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The mechanism of PfCoronin-mediated resistance was resolved by tying the protein to PfActin, hemoglobin-trafficking compartments, and endocytosis.\",\n      \"evidence\": \"Co-immunoprecipitation of PfCoronin\\u2013PfActin, live/fixed localization, CRISPR/Cas9 introduction of resistance mutations, and hemoglobin uptake and preDV morphology assays (preprint)\",\n      \"pmids\": [\"38187525\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"How preDV compartment couples to the digestive vacuole not fully defined\", \"Quantitative link from reduced uptake to heme-dependent drug activation not directly measured\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The genetic requirement and pathway relationship were formalized, showing PfCoronin is dispensable and acts in a ring-stage endocytic pathway that converges with PfKelch13 on heme availability.\",\n      \"evidence\": \"Genetic knockout for dispensability, allelic replacement, PfCoronin\\u2013PfActin co-immunoprecipitation, localization imaging, hemoglobin uptake assays, and epistasis with PfKelch13 (preprint)\",\n      \"pmids\": [\"40964400\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Distinct cellular regions of PfCoronin vs PfKelch13 action not spatially resolved in detail\", \"Structural basis for mutation-driven loss of PfActin interaction unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How resistance-associated substitutions in the \\u03b2-propeller structurally disrupt PfActin binding and preDV endocytosis, and how this quantitatively limits heme-dependent artemisinin activation, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structure of mutant PfCoronin\\u2013PfActin complex\", \"Direct measurement of heme flux downstream of reduced hemoglobin uptake absent\", \"Mechanistic overlap with PfKelch13 endocytosis not molecularly defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051015\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"GO:0051017\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005543\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0020020\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006897\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0071973\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0030036\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfActin\",\n      \"PfKelch13 (functionally convergent pathway, not physical partner)\"\n    ],\n    \"other_free_text\": [\n      \"N-terminal WD40/\\u03b2-propeller domain mediates F-actin binding and bundling [#1]\",\n      \"Membrane association attributed to PI(4,5)P2 binding [#1]\",\n      \"In P. berghei sporozoites, calcium- and PKA-linked signaling controls coronin relocalization and actin filament disassembly during gliding motility [#2]\",\n      \"Non-essential for parasite viability; resistance-associated mutations impair PfActin homeostasis and ring-stage hemoglobin uptake, conferring partial artemisinin resistance distinct from PfKelch13 [#4, #5, #6]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1251200","name":null,"product":"coronin","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1464100","name":null,"product":"coronin","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1471200","name":null,"product":"coronin, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}