{"gene":"PF3D7_1231400","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2021,"finding":"ICM1 (PF3D7_1231400) is a multipass membrane protein with homology to transporters and calcium channels that is tightly associated (physically interacts) with PKG in both asexual blood stages and transmission stages of Plasmodium falciparum and P. berghei, as demonstrated by co-immunoprecipitation and proteomic analyses.","method":"Co-immunoprecipitation / protein interaction proteomics","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP reported in a single lab with multiple life-cycle stages examined; interaction confirmed across two Plasmodium species","pmids":["33762339"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"finding":"ICM1 undergoes multiple phosphorylation events that are dependent on PKG activity, as revealed by phosphoproteomic analysis comparing wild-type and PKG-inhibited parasites.","method":"Phosphoproteomic analysis (mass spectrometry) with PKG inhibition","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics with PKG inhibition in a single lab; PKG-dependency established by chemical perturbation","pmids":["33762339"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"finding":"Stage-specific depletion of ICM1 in P. berghei prevents gametogenesis due to a block in intracellular calcium mobilization, establishing ICM1 as essential for PKG-dependent calcium release required for gamete formation.","method":"Stage-specific conditional knockdown / genetic depletion with calcium imaging readout","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic depletion in two Plasmodium species with direct intracellular calcium mobilization measurements as functional readout, supported by phosphoproteomics","pmids":["33762339"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"finding":"Conditional loss of ICM1 in P. falciparum results in severely reduced intracellular calcium mobilization, defective merozoite egress, and lack of invasion, demonstrating ICM1 is required for PKG-dependent calcium signaling in asexual blood stages.","method":"Conditional knockdown / genetic depletion with calcium imaging, egress, and invasion assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic depletion with multiple orthogonal functional readouts (calcium mobilization, egress, invasion) in a single rigorous study","pmids":["33762339"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Conditional knockout of ICM1 in P. falciparum did not prevent exocytosis of SUB1 into the parasitophorous vacuole, indicating that ICM1-dependent calcium mobilization is not required for exoneme exocytosis during egress.","method":"Conditional knockout with fluorescent exocytosis reporter and SUB1 localization assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — negative finding reported from conditional KO with specific molecular readout (SUB1 exocytosis) in a single study; establishes a functional boundary for ICM1 activity","pmids":["42113900"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"A sub-population of P. falciparum PKG molecules is associated with the ER membrane, possibly through interaction with ICM1, suggesting ICM1 serves as a membrane anchor or scaffold for PKG at the ER.","method":"Genetic and biochemical approaches (cited as previously established interaction)","journal":"PLoS pathogens","confidence":"Low","confidence_rationale":"Tier 3 / Weak — inference from cited prior work (Balestra et al. 2021) referenced in discussion context; no new direct experiment in this paper for this specific claim","pmids":["38935780"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"ICM1 (PF3D7_1231400) is a multipass transmembrane protein that physically interacts with and is phosphorylated by PKG; it functions downstream of PKG to mobilize calcium from intracellular stores, and its conditional loss in P. falciparum and P. berghei severely impairs intracellular calcium release, blocking merozoite egress, invasion, and gametogenesis, though it is dispensable for exoneme exocytosis."},"narrative":{"mechanistic_narrative":"ICM1 (PF3D7_1231400) is a multipass membrane protein that acts downstream of PKG to mobilize calcium from intracellular stores, coupling PKG signaling to the calcium-dependent transitions of the Plasmodium life cycle [PMID:33762339]. It physically associates with PKG across asexual blood stages and transmission stages of both P. falciparum and P. berghei, and is itself phosphorylated at multiple sites in a PKG-activity-dependent manner, placing it as a direct effector within the PKG signaling module [PMID:33762339]. Functionally, conditional depletion of ICM1 collapses intracellular calcium mobilization: in P. berghei this blocks gametogenesis, while in P. falciparum it impairs merozoite egress and abolishes invasion [PMID:33762339]. This calcium-mobilizing role is selective rather than global to egress, since ICM1 loss in P. falciparum does not prevent exoneme exocytosis of SUB1 into the parasitophorous vacuole, defining a boundary on the processes it controls [PMID:42113900]. Beyond its membership in the PKG-ICM1 module and its role in calcium release, the transport or channel activity implied by its sequence has not been directly characterized in the available corpus.","teleology":[{"year":2021,"claim":"Establishing whether PKG operates through a dedicated membrane effector was unknown; identifying ICM1 as a tight PKG-associated multipass membrane protein defined a physical PKG signaling module conserved across species and life-cycle stages.","evidence":"Reciprocal co-immunoprecipitation and interaction proteomics in asexual and transmission stages of P. falciparum and P. berghei","pmids":["33762339"],"confidence":"Medium","gaps":["Interaction shown by co-IP/proteomics in a single lab without structural mapping of the interface","Whether the association is direct or bridged by other complex members is not resolved","The transporter/channel activity implied by homology was not tested biochemically"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"claim":"Whether ICM1 is a PKG substrate or merely a binding partner was open; PKG-dependent phosphorylation placed ICM1 as a regulated node within the pathway.","evidence":"Phosphoproteomic mass spectrometry comparing wild-type and PKG-inhibited parasites","pmids":["33762339"],"confidence":"Medium","gaps":["PKG-dependency established by chemical inhibition rather than direct kinase reconstitution","Functional consequence of the specific phosphosites was not tested by phosphomutants"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2021,"claim":"The physiological output of the PKG-ICM1 association was unknown; conditional depletion showed ICM1 is required for intracellular calcium mobilization driving gametogenesis, egress, and invasion.","evidence":"Stage-specific conditional depletion with calcium imaging in P. berghei (gametogenesis) and calcium, egress, and invasion assays in P. falciparum","pmids":["33762339"],"confidence":"High","gaps":["Whether ICM1 itself transports calcium or gates another channel was not directly demonstrated","The intracellular store(s) mobilized were not molecularly resolved"],"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Whether ICM1-dependent calcium release governs all egress-associated secretion was open; ICM1 loss did not block SUB1 exoneme exocytosis, defining a functional boundary for ICM1 activity.","evidence":"Conditional knockout with fluorescent exocytosis reporter and SUB1 localization in P. falciparum","pmids":["42113900"],"confidence":"Medium","gaps":["Negative finding from a single study using one exocytosis readout","The full set of calcium-dependent secretory events that do require ICM1 is not delineated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"The subcellular site of PKG-ICM1 action was unclear; an ER-associated PKG sub-population possibly anchored by ICM1 was inferred, pointing to the ER as a candidate signaling locus.","evidence":"Inference in discussion citing prior interaction work; no new direct experiment for this claim in P. falciparum","pmids":["38935780"],"confidence":"Low","gaps":["Claim is an inference from cited prior work, not a new direct experiment; ICM1 ER localization not independently demonstrated here","Direct evidence that ICM1 anchors PKG to the ER is absent"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether ICM1 is itself the calcium-transporting/channel entity or a regulatory scaffold that gates a distinct store-release machinery remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstitution or electrophysiological demonstration of ICM1 transport/channel activity","No structural model of ICM1 or its PKG interface","The identity of the calcium store and any partner transporters are uncharacterized"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PKG-ICM1 signaling module"],"partners":["PKG (CGMP-DEPENDENT PROTEIN KINASE)"],"other_free_text":["Multipass transmembrane protein with sequence homology to transporters and calcium channels [#0]","Phosphorylated at multiple sites in a PKG-activity-dependent manner [#1]","Required for intracellular calcium mobilization underlying gametogenesis in P. berghei and merozoite egress and invasion in P. falciparum [#2, #3]","Dispensable for SUB1 exoneme exocytosis into the parasitophorous vacuole in P. falciparum [#4]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"33762339","id":"PMC_33762339","title":"Ca2+ signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33762339","citation_count":51,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39162502","id":"PMC_39162502","title":"Orthologs of Plasmodium ICM1 are dispensable for Ca2+ mobilization in Toxoplasma gondii.","date":"2024","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/39162502","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":true,"competing_organism_match":"Toxoplasma","competing_organism_only":true},{"pmid":"41084330","id":"","title":"Plasmodium falciparum gametogenesis essential protein 1 (GEP1) is a transmission-blocking target.","date":"2025","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/41084330","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42113900","id":"","title":"Spatiotemporal dynamics of signal dependent exocytosis and parasitophorous vacuolar membrane rupture during Plasmodium falciparum egress.","date":"2026","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/42113900","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38935780","id":"","title":"Activation loop phosphorylation and cGMP saturation of PKG regulate egress of malaria parasites.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/38935780","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40163471","id":"","title":"Advances in the dissection of Anopheles-Plasmodium interactions.","date":"2025","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/40163471","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35782151","id":"","title":"Gametogenesis in Plasmodium: Delving Deeper to Connect the Dots.","date":"2022","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35782151","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35811673","id":"","title":"Updated List of Transport Proteins in Plasmodium falciparum.","date":"2022","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35811673","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39808636","id":"","title":"The malaria parasite PP1 phosphatase controls the initiation of the egress pathway of asexual blood-stages by regulating the rounding-up of the vacuole.","date":"2025","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/39808636","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35638735","id":"","title":"PfARID Regulates P. falciparum Malaria Parasite Male Gametogenesis and Female Fertility and Is Critical for Parasite Transmission to the Mosquito Vector.","date":"2022","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/35638735","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34724830","id":"","title":"Plasmodium falciparum Calcium-Dependent Protein Kinase 4 is Critical for Male Gametogenesis and Transmission to the Mosquito Vector.","date":"2021","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/34724830","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34395314","id":"","title":"Calcium in the Backstage of Malaria Parasite Biology.","date":"2021","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34395314","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35755845","id":"","title":"Adapt or Die: Targeting Unique Transmission-Stage Biology for Malaria Elimination.","date":"2022","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35755845","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ICM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13918,"output_tokens":1508,"usd":0.032187,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6527,"output_tokens":2650,"usd":0.049443,"stage2_stop_reason":"end_turn"},"total_usd":0.08163,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"ICM1 (PF3D7_1231400) is a multipass membrane protein with homology to transporters and calcium channels that is tightly associated (physically interacts) with PKG in both asexual blood stages and transmission stages of Plasmodium falciparum and P. berghei, as demonstrated by co-immunoprecipitation and proteomic analyses.\",\n      \"method\": \"Co-immunoprecipitation / protein interaction proteomics\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP reported in a single lab with multiple life-cycle stages examined; interaction confirmed across two Plasmodium species\",\n      \"pmids\": [\"33762339\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ICM1 undergoes multiple phosphorylation events that are dependent on PKG activity, as revealed by phosphoproteomic analysis comparing wild-type and PKG-inhibited parasites.\",\n      \"method\": \"Phosphoproteomic analysis (mass spectrometry) with PKG inhibition\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics with PKG inhibition in a single lab; PKG-dependency established by chemical perturbation\",\n      \"pmids\": [\"33762339\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Stage-specific depletion of ICM1 in P. berghei prevents gametogenesis due to a block in intracellular calcium mobilization, establishing ICM1 as essential for PKG-dependent calcium release required for gamete formation.\",\n      \"method\": \"Stage-specific conditional knockdown / genetic depletion with calcium imaging readout\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic depletion in two Plasmodium species with direct intracellular calcium mobilization measurements as functional readout, supported by phosphoproteomics\",\n      \"pmids\": [\"33762339\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional loss of ICM1 in P. falciparum results in severely reduced intracellular calcium mobilization, defective merozoite egress, and lack of invasion, demonstrating ICM1 is required for PKG-dependent calcium signaling in asexual blood stages.\",\n      \"method\": \"Conditional knockdown / genetic depletion with calcium imaging, egress, and invasion assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic depletion with multiple orthogonal functional readouts (calcium mobilization, egress, invasion) in a single rigorous study\",\n      \"pmids\": [\"33762339\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional knockout of ICM1 in P. falciparum did not prevent exocytosis of SUB1 into the parasitophorous vacuole, indicating that ICM1-dependent calcium mobilization is not required for exoneme exocytosis during egress.\",\n      \"method\": \"Conditional knockout with fluorescent exocytosis reporter and SUB1 localization assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — negative finding reported from conditional KO with specific molecular readout (SUB1 exocytosis) in a single study; establishes a functional boundary for ICM1 activity\",\n      \"pmids\": [\"42113900\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A sub-population of P. falciparum PKG molecules is associated with the ER membrane, possibly through interaction with ICM1, suggesting ICM1 serves as a membrane anchor or scaffold for PKG at the ER.\",\n      \"method\": \"Genetic and biochemical approaches (cited as previously established interaction)\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — inference from cited prior work (Balestra et al. 2021) referenced in discussion context; no new direct experiment in this paper for this specific claim\",\n      \"pmids\": [\"38935780\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"ICM1 (PF3D7_1231400) is a multipass transmembrane protein that physically interacts with and is phosphorylated by PKG; it functions downstream of PKG to mobilize calcium from intracellular stores, and its conditional loss in P. falciparum and P. berghei severely impairs intracellular calcium release, blocking merozoite egress, invasion, and gametogenesis, though it is dispensable for exoneme exocytosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ICM1 (PF3D7_1231400) is a multipass membrane protein that acts downstream of PKG to mobilize calcium from intracellular stores, coupling PKG signaling to the calcium-dependent transitions of the Plasmodium life cycle [#0, #3]. It physically associates with PKG across asexual blood stages and transmission stages of both P. falciparum and P. berghei, and is itself phosphorylated at multiple sites in a PKG-activity-dependent manner, placing it as a direct effector within the PKG signaling module [#0, #1]. Functionally, conditional depletion of ICM1 collapses intracellular calcium mobilization: in P. berghei this blocks gametogenesis, while in P. falciparum it impairs merozoite egress and abolishes invasion [#2, #3]. This calcium-mobilizing role is selective rather than global to egress, since ICM1 loss in P. falciparum does not prevent exoneme exocytosis of SUB1 into the parasitophorous vacuole, defining a boundary on the processes it controls [#4]. Beyond its membership in the PKG-ICM1 module and its role in calcium release, the transport or channel activity implied by its sequence has not been directly characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing whether PKG operates through a dedicated membrane effector was unknown; identifying ICM1 as a tight PKG-associated multipass membrane protein defined a physical PKG signaling module conserved across species and life-cycle stages.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and interaction proteomics in asexual and transmission stages of P. falciparum and P. berghei\",\n      \"pmids\": [\"33762339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction shown by co-IP/proteomics in a single lab without structural mapping of the interface\",\n        \"Whether the association is direct or bridged by other complex members is not resolved\",\n        \"The transporter/channel activity implied by homology was not tested biochemically\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether ICM1 is a PKG substrate or merely a binding partner was open; PKG-dependent phosphorylation placed ICM1 as a regulated node within the pathway.\",\n      \"evidence\": \"Phosphoproteomic mass spectrometry comparing wild-type and PKG-inhibited parasites\",\n      \"pmids\": [\"33762339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PKG-dependency established by chemical inhibition rather than direct kinase reconstitution\",\n        \"Functional consequence of the specific phosphosites was not tested by phosphomutants\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The physiological output of the PKG-ICM1 association was unknown; conditional depletion showed ICM1 is required for intracellular calcium mobilization driving gametogenesis, egress, and invasion.\",\n      \"evidence\": \"Stage-specific conditional depletion with calcium imaging in P. berghei (gametogenesis) and calcium, egress, and invasion assays in P. falciparum\",\n      \"pmids\": [\"33762339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ICM1 itself transports calcium or gates another channel was not directly demonstrated\",\n        \"The intracellular store(s) mobilized were not molecularly resolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether ICM1-dependent calcium release governs all egress-associated secretion was open; ICM1 loss did not block SUB1 exoneme exocytosis, defining a functional boundary for ICM1 activity.\",\n      \"evidence\": \"Conditional knockout with fluorescent exocytosis reporter and SUB1 localization in P. falciparum\",\n      \"pmids\": [\"42113900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative finding from a single study using one exocytosis readout\",\n        \"The full set of calcium-dependent secretory events that do require ICM1 is not delineated\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The subcellular site of PKG-ICM1 action was unclear; an ER-associated PKG sub-population possibly anchored by ICM1 was inferred, pointing to the ER as a candidate signaling locus.\",\n      \"evidence\": \"Inference in discussion citing prior interaction work; no new direct experiment for this claim in P. falciparum\",\n      \"pmids\": [\"38935780\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Claim is an inference from cited prior work, not a new direct experiment; ICM1 ER localization not independently demonstrated here\",\n        \"Direct evidence that ICM1 anchors PKG to the ER is absent\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether ICM1 is itself the calcium-transporting/channel entity or a regulatory scaffold that gates a distinct store-release machinery remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstitution or electrophysiological demonstration of ICM1 transport/channel activity\",\n        \"No structural model of ICM1 or its PKG interface\",\n        \"The identity of the calcium store and any partner transporters are uncharacterized\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0019901\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005789\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0051209\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0007338\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"PKG-ICM1 signaling module\"\n    ],\n    \"partners\": [\n      \"PKG (cGMP-dependent protein kinase)\"\n    ],\n    \"other_free_text\": [\n      \"Multipass transmembrane protein with sequence homology to transporters and calcium channels [#0]\",\n      \"Phosphorylated at multiple sites in a PKG-activity-dependent manner [#1]\",\n      \"Required for intracellular calcium mobilization underlying gametogenesis in P. berghei and merozoite egress and invasion in P. falciparum [#2, #3]\",\n      \"Dispensable for SUB1 exoneme exocytosis into the parasitophorous vacuole in P. falciparum [#4]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1231400","name":null,"product":"membrane protein ICM1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1446100","name":null,"product":"membrane protein ICM1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1450800","name":null,"product":"membrane protein ICM1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ICM1","evaluation":null}