{"gene":"TG_242070","gene_symbol":"PKAR1","run_date":"2026-09-08T12:58:25","timeline":{"discoveries":[{"year":2018,"finding":"PKAr1 (PKAR1) sequesters the PKA catalytic subunit 1 (PKAc1) to the parasite periphery via dual acylation of PKAr1, establishing PKAr1 as a membrane-targeting anchor for the PKA holoenzyme.","method":"Genetic/biochemical demonstration of dual acylation of PKAr1 and its role in peripheral localization of PKAc1","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence described in a single lab study; dual acylation and peripheral sequestration of PKAc1 by PKAr1 shown, but abstract-level detail limits full method assessment","pmids":["30208022"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2018,"finding":"PKAr1-anchored PKAc1 at the parasite periphery suppresses cytosolic Ca2+ signalling upon host cell invasion; genetic depletion of PKAc1 prevents rapid down-regulation of cytosolic [Ca2+] after invasion, causing newly invaded parasites to exit host cells in a PLP-1-dependent manner.","method":"Genetic depletion (conditional knockdown) of PKAc1 with cytosolic Ca2+ measurement and egress phenotype readout","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic depletion with two orthogonal phenotypic readouts (Ca2+ dynamics and egress assay), single lab but multiple functional validations","pmids":["30208022"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2018,"finding":"Loss of PKAc1 (anchored by PKAr1) sensitises parasites to cGMP-induced Ca2+ signalling, demonstrating a functional link between the cAMP/PKA axis and cGMP signalling modalities in Toxoplasma.","method":"Pharmacological cGMP stimulation combined with genetic depletion of PKAc1 and Ca2+ signalling readout","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistasis between cAMP/PKA and cGMP pathways shown by single lab with pharmacological and genetic tools, but single study","pmids":["30208022"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"PKAr1 (the PKA regulatory subunit 1) anchors the PKA holoenzyme to the parasite periphery via dual acylation, positioning PKAc1 to suppress cytosolic Ca2+ signalling after host cell invasion and thereby prevent premature egress; it also functionally links cAMP/PKA signalling to the cGMP-Ca2+ signalling axis in Toxoplasma gondii."},"narrative":{"mechanistic_narrative":"PKAr1 is the regulatory subunit of the Toxoplasma gondii PKA holoenzyme that couples cAMP/PKA signalling to the control of intracellular Ca2+ and the timing of host-cell egress [PMID:30208022]. Through dual acylation, PKAr1 anchors the PKA catalytic subunit PKAc1 to the parasite periphery, functioning as a membrane-targeting scaffold for the holoenzyme [PMID:30208022]. Peripheral PKAr1-anchored PKAc1 activity suppresses cytosolic Ca2+ signalling immediately after host-cell invasion; depletion of PKAc1 blocks the rapid post-invasion down-regulation of cytosolic Ca2+, triggering premature, PLP-1-dependent exit of newly invaded parasites [PMID:30208022]. This activity also opposes cGMP-induced Ca2+ signalling, placing the cAMP/PKA axis in functional opposition to the cGMP-Ca2+ signalling modality [PMID:30208022]. Mechanistic detail beyond this signalling role, including direct PKAc1 substrates and the biochemistry of PKAr1 acylation, has not been characterized in the available corpus.","teleology":[{"year":2018,"claim":"Establishing how the PKA holoenzyme is spatially organized in the parasite, dual acylation of PKAr1 was shown to anchor PKAc1 to the parasite periphery, defining PKAr1 as the membrane-targeting subunit of PKA.","evidence":"Genetic/biochemical demonstration of PKAr1 dual acylation and peripheral localization of PKAc1 in T. gondii","pmids":["30208022"],"confidence":"Medium","gaps":["Acylation sites and modifying enzymes not defined","Structural basis of PKAc1 sequestration by PKAr1 not resolved"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2018,"claim":"To determine the functional output of peripheral PKA anchoring, conditional depletion of PKAc1 revealed that PKAr1-anchored PKA suppresses cytosolic Ca2+ after invasion to prevent premature egress, linking PKA activity to control of the parasite lytic cycle.","evidence":"Conditional knockdown of PKAc1 with cytosolic Ca2+ measurement and PLP-1-dependent egress phenotype readout","pmids":["30208022"],"confidence":"High","gaps":["Direct PKAc1 substrates mediating Ca2+ suppression not identified","Mechanism connecting PKA activity to PLP-1-dependent egress unresolved"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2018,"claim":"To test crosstalk between second-messenger pathways, combining cGMP stimulation with PKAc1 depletion showed that loss of PKA sensitizes parasites to cGMP-induced Ca2+, establishing functional opposition between the cAMP/PKA and cGMP-Ca2+ axes.","evidence":"Pharmacological cGMP stimulation combined with genetic PKAc1 depletion and Ca2+ signalling readout in T. gondii","pmids":["30208022"],"confidence":"Medium","gaps":["Molecular node of convergence between cAMP/PKA and cGMP pathways not identified","Single study with pharmacological tools"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"The direct substrates of PKAc1 and the biochemical mechanism by which PKA suppresses cytosolic Ca2+ and integrates cGMP signalling remain unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No PKAc1 substrate identified","No structural model of the PKAr1-PKAc1 holoenzyme","cAMP-dependent regulation of PKAr1-PKAc1 dissociation not characterized in the corpus"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PKA holoenzyme (PKAr1-PKAc1)"],"partners":["PKAC1 (PKA CATALYTIC SUBUNIT 1)"],"other_free_text":["PKAr1 is dually acylated, which targets the PKA holoenzyme to the parasite periphery [#0].","PKAr1-anchored PKAc1 suppresses post-invasion cytosolic Ca2+ to prevent premature, PLP-1-dependent egress [#1].","PKA activity functionally opposes cGMP-induced Ca2+ signalling [#2]."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"30208022","id":"PMC_30208022","title":"Protein kinase A negatively regulates Ca2+ signalling in Toxoplasma gondii.","date":"2018","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/30208022","citation_count":55,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2917,"output_tokens":875,"usd":0.010938,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5709,"output_tokens":2139,"usd":0.04101,"stage2_stop_reason":"end_turn"},"total_usd":0.051948,"stage1_batch_id":"msgbatch_01TEPNZ4MCzJ7xtsNwosiDRk","stage2_batch_id":"msgbatch_01FQShM7n1sfCr4pWTDShmki","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"PKAr1 (PKAR1) sequesters the PKA catalytic subunit 1 (PKAc1) to the parasite periphery via dual acylation of PKAr1, establishing PKAr1 as a membrane-targeting anchor for the PKA holoenzyme.\",\n      \"method\": \"Genetic/biochemical demonstration of dual acylation of PKAr1 and its role in peripheral localization of PKAc1\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence described in a single lab study; dual acylation and peripheral sequestration of PKAc1 by PKAr1 shown, but abstract-level detail limits full method assessment\",\n      \"pmids\": [\"30208022\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PKAr1-anchored PKAc1 at the parasite periphery suppresses cytosolic Ca2+ signalling upon host cell invasion; genetic depletion of PKAc1 prevents rapid down-regulation of cytosolic [Ca2+] after invasion, causing newly invaded parasites to exit host cells in a PLP-1-dependent manner.\",\n      \"method\": \"Genetic depletion (conditional knockdown) of PKAc1 with cytosolic Ca2+ measurement and egress phenotype readout\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic depletion with two orthogonal phenotypic readouts (Ca2+ dynamics and egress assay), single lab but multiple functional validations\",\n      \"pmids\": [\"30208022\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of PKAc1 (anchored by PKAr1) sensitises parasites to cGMP-induced Ca2+ signalling, demonstrating a functional link between the cAMP/PKA axis and cGMP signalling modalities in Toxoplasma.\",\n      \"method\": \"Pharmacological cGMP stimulation combined with genetic depletion of PKAc1 and Ca2+ signalling readout\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistasis between cAMP/PKA and cGMP pathways shown by single lab with pharmacological and genetic tools, but single study\",\n      \"pmids\": [\"30208022\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PKAr1 (the PKA regulatory subunit 1) anchors the PKA holoenzyme to the parasite periphery via dual acylation, positioning PKAc1 to suppress cytosolic Ca2+ signalling after host cell invasion and thereby prevent premature egress; it also functionally links cAMP/PKA signalling to the cGMP-Ca2+ signalling axis in Toxoplasma gondii.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PKAr1 is the regulatory subunit of the Toxoplasma gondii PKA holoenzyme that couples cAMP/PKA signalling to the control of intracellular Ca2+ and the timing of host-cell egress [#0, #1]. Through dual acylation, PKAr1 anchors the PKA catalytic subunit PKAc1 to the parasite periphery, functioning as a membrane-targeting scaffold for the holoenzyme [#0]. Peripheral PKAr1-anchored PKAc1 activity suppresses cytosolic Ca2+ signalling immediately after host-cell invasion; depletion of PKAc1 blocks the rapid post-invasion down-regulation of cytosolic Ca2+, triggering premature, PLP-1-dependent exit of newly invaded parasites [#1]. This activity also opposes cGMP-induced Ca2+ signalling, placing the cAMP/PKA axis in functional opposition to the cGMP-Ca2+ signalling modality [#2]. Mechanistic detail beyond this signalling role, including direct PKAc1 substrates and the biochemistry of PKAr1 acylation, has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing how the PKA holoenzyme is spatially organized in the parasite, dual acylation of PKAr1 was shown to anchor PKAc1 to the parasite periphery, defining PKAr1 as the membrane-targeting subunit of PKA.\",\n      \"evidence\": \"Genetic/biochemical demonstration of PKAr1 dual acylation and peripheral localization of PKAc1 in T. gondii\",\n      \"pmids\": [\"30208022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acylation sites and modifying enzymes not defined\", \"Structural basis of PKAc1 sequestration by PKAr1 not resolved\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"To determine the functional output of peripheral PKA anchoring, conditional depletion of PKAc1 revealed that PKAr1-anchored PKA suppresses cytosolic Ca2+ after invasion to prevent premature egress, linking PKA activity to control of the parasite lytic cycle.\",\n      \"evidence\": \"Conditional knockdown of PKAc1 with cytosolic Ca2+ measurement and PLP-1-dependent egress phenotype readout\",\n      \"pmids\": [\"30208022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PKAc1 substrates mediating Ca2+ suppression not identified\", \"Mechanism connecting PKA activity to PLP-1-dependent egress unresolved\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"To test crosstalk between second-messenger pathways, combining cGMP stimulation with PKAc1 depletion showed that loss of PKA sensitizes parasites to cGMP-induced Ca2+, establishing functional opposition between the cAMP/PKA and cGMP-Ca2+ axes.\",\n      \"evidence\": \"Pharmacological cGMP stimulation combined with genetic PKAc1 depletion and Ca2+ signalling readout in T. gondii\",\n      \"pmids\": [\"30208022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular node of convergence between cAMP/PKA and cGMP pathways not identified\", \"Single study with pharmacological tools\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct substrates of PKAc1 and the biochemical mechanism by which PKA suppresses cytosolic Ca2+ and integrates cGMP signalling remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No PKAc1 substrate identified\", \"No structural model of the PKAr1-PKAc1 holoenzyme\", \"cAMP-dependent regulation of PKAr1-PKAc1 dissociation not characterized in the corpus\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0034237\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0008179\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0071944\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0034199\", \"supporting_discovery_ids\": [1, 2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0051279\", \"supporting_discovery_ids\": [1, 2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\"PKA holoenzyme (PKAr1-PKAc1)\"],\n    \"partners\": [\"PKAc1 (PKA catalytic subunit 1)\"],\n    \"other_free_text\": [\n      \"PKAr1 is dually acylated, which targets the PKA holoenzyme to the parasite periphery [#0].\",\n      \"PKAr1-anchored PKAc1 suppresses post-invasion cytosolic Ca2+ to prevent premature, PLP-1-dependent egress [#1].\",\n      \"PKA activity functionally opposes cGMP-induced Ca2+ signalling [#2].\"\n    ]\n  },\n  \"strain_conflicts\": []\n}\n```","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_242070","name":"PKAR1","product":"cAMP-dependent protein kinase regulatory subunit 1","uniprot_acc":"A0A125YLM6","chromosome":"TGME49_chrVI","start_pos":1866928},{"strain":"GT1","gene_id":"TGGT1_242070","name":null,"product":"cAMP-dependent protein kinase regulatory subunit","uniprot_acc":null,"chromosome":"TGGT1_chrVI","start_pos":1804976},{"strain":"RH88","gene_id":"TGRH88_029860","name":null,"product":"cAMP-dependent protein kinase regulatory subunit","uniprot_acc":null,"chromosome":"CM023087","start_pos":1839477},{"strain":"VEG","gene_id":"TGVEG_242070","name":null,"product":"cAMP-dependent protein kinase regulatory subunit","uniprot_acc":"A0A0F7UTU3","chromosome":"TGVEG_chrVI","start_pos":1881430}]}