{"gene":"PF3D7_1361800","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2016,"finding":"GAC (glideosome-associated connector) in Toxoplasma gondii and Plasmodium berghei binds to and stabilizes filamentous actin through its N-terminal armadillo domain, connects micronemal transmembrane adhesins (TgMIC2) to the actomyosin system, and localizes to the apical pole in invasive stages; its PH domain binds phosphatidic acid, a lipid mediator associated with microneme exocytosis. Apical positioning of TgGAC depends on the apical lysine methyltransferase TgAKMT. Loss-of-function experiments established roles in gliding motility, invasion, and egress.","method":"Co-immunoprecipitation, pulldown assays, live imaging/IFA for localization, actin-binding assays, lipid-binding assays with PH domain, genetic knockdown/conditional knockout with phenotypic readout (gliding motility, invasion, egress)","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, actin-binding assay, lipid-binding assay, localization, functional knockdown) in a single rigorous study, with both T. gondii and P. berghei orthologs examined","pmids":["27978434"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2025,"finding":"P. berghei GAC (PbGAC; PbANKA_1137800) localizes predominantly to the extreme apical region of the merozoite, binds heparin and the erythrocyte surface in a heparan sulfate-dependent manner, and interacts by immunoprecipitation/mass spectrometry with multiple secreted proteins involved in erythrocyte invasion. Antibodies against PbGAC inhibit invasion in murine models.","method":"Western blotting, immunofluorescence, flow cytometry, heparinase II treatment (heparan sulfate-binding assay), heparin-sepharose pulldown, immunoprecipitation followed by global mass spectrometry, passive immunization invasion inhibition assay","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (binding assays, IP-MS, functional inhibition) in a single lab study; replication not yet established","pmids":["41152982"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":"ANKA"}]},{"year":2022,"finding":"Cryo-EM structural analysis of the P. falciparum glideosome complex indicates that GAC (with a Dmax ~25 nm in solution) physically links actin filaments to the plasma membrane and imposes significant geometric/steric constraints on the arrangement of the actomyosin motor within the sub-pellicular compartment (~30 nm between IMC and plasma membrane).","method":"Cryo-EM structural determination of PfActomyosin complex; structural modeling of GAC dimensions cited from prior biophysical data","journal":"PLoS pathogens","confidence":"Low","confidence_rationale":"Tier 3 / Weak — structural inference about GAC's role is derived from modeling/dimensional considerations in a paper primarily characterizing PfMyoA:PfAct1; no direct experiment on GAC itself was performed in this study","pmids":["35377914"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"GAC (PF3D7_1361800) is a conserved armadillo/PH domain-containing apical connector protein that stabilizes filamentous actin via its N-terminal domain, binds the cytoplasmic tails of micronemal transmembrane adhesins (e.g., MTRAP/MIC2), and anchors to the inner plasma membrane leaflet via phosphatidic acid recognition by its PH domain, thereby physically coupling extracellular adhesion to the intracellular actomyosin motor to power gliding motility, host cell invasion, and egress; in P. berghei, GAC additionally engages heparan sulfate proteoglycans on the erythrocyte surface and interacts with multiple invasion-related secreted proteins at the merozoite apical tip."},"narrative":{"mechanistic_narrative":"GAC (PF3D7_1361800) is a conserved apical connector protein of apicomplexan invasive stages that physically couples extracellular adhesion to the intracellular actomyosin motor to drive gliding motility, host cell invasion, and egress [PMID:27978434]. Characterized in the Toxoplasma gondii and Plasmodium berghei orthologs, GAC binds and stabilizes filamentous actin through its N-terminal armadillo domain, engages the cytoplasmic tail of the micronemal transmembrane adhesin TgMIC2, and anchors to membranes through PH-domain recognition of phosphatidic acid, with its apical positioning depending on the lysine methyltransferase TgAKMT [PMID:27978434]. In P. berghei, the ortholog concentrates at the extreme apical tip of the merozoite, binds the erythrocyte surface in a heparan sulfate-dependent manner, associates by IP-MS with multiple secreted invasion proteins, and is a target of invasion-inhibitory antibodies [PMID:41152982]. No direct experimental characterization of the P. falciparum PF3D7_1361800 protein itself is present in the corpus beyond a structural inference that it bridges actin filaments to the plasma membrane within the geometrically constrained sub-pellicular compartment [PMID:35377914].","teleology":[{"year":2016,"claim":"Established the founding molecular function of GAC: how does extracellular adhesion transmit force to the intracellular motor? GAC was shown to be the physical bridge linking micronemal adhesins to actomyosin.","evidence":"Co-IP, actin- and lipid-binding assays, localization, and conditional knockout with gliding/invasion/egress readouts in T. gondii and P. berghei","pmids":["27978434"],"confidence":"High","gaps":["No direct experiment on the P. falciparum PF3D7_1361800 ortholog","Structural basis of simultaneous actin, adhesin-tail, and phosphatidic acid engagement not resolved","Mechanism by which TgAKMT controls apical positioning undefined"],"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2022,"claim":"Addressed how GAC fits within the crowded sub-pellicular space: structural modeling of the P. falciparum glideosome inferred that GAC's elongated dimensions bridge actin to the plasma membrane and constrain motor geometry.","evidence":"Cryo-EM of the PfActomyosin complex with dimensional modeling of GAC cited from prior biophysical data; no direct experiment on GAC performed","pmids":["35377914"],"confidence":"Low","gaps":["Inference only — no direct structural or functional experiment on PF3D7_1361800 was performed in this study","GAC's geometry within the assembled glideosome not directly visualized","Whether P. falciparum GAC behaves as the orthologs do is not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Extended GAC's role beyond the intracellular motor connector: does GAC also directly contact the host cell? The P. berghei ortholog was shown to bind the erythrocyte surface via heparan sulfate and to be an invasion-inhibitory antibody target.","evidence":"Western blot, IFA, flow cytometry, heparinase II and heparin-sepharose binding assays, IP-MS, and passive immunization invasion-inhibition in murine models","pmids":["41152982"],"confidence":"Medium","gaps":["Single-lab study; replication not yet established","Direct host-parasite binding partner of GAC on the erythrocyte not identified","Whether apparent apical-surface exposure reflects genuine extracellular display versus co-purified secreted proteins is unresolved"],"attribution":[{"species":"Plasmodium berghei","strain":"ANKA"}]},{"year":null,"claim":"Whether the P. falciparum PF3D7_1361800 protein directly recapitulates the actin-binding, adhesin-linking, and lipid-anchoring activities defined in orthologs, and whether it engages host-cell ligands, remains experimentally unaddressed in this corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct biochemical or genetic characterization of PF3D7_1361800 itself","No structural model of the P. falciparum protein","Host-cell binding shown only for the P. berghei ortholog"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Glideosome / actomyosin motor complex (as connector) [#0, #2]"],"partners":["FILAMENTOUS ACTIN (F-ACTIN) VIA N-TERMINAL ARMADILLO DOMAIN [#0]","TGMIC2 MICRONEMAL ADHESIN CYTOPLASMIC TAIL [#0]","PHOSPHATIDIC ACID (PH DOMAIN) [#0]","TGAKMT (APICAL LYSINE METHYLTRANSFERASE, CONTROLS APICAL POSITIONING) [#0]","HEPARAN SULFATE / HEPARIN ON THE ERYTHROCYTE SURFACE (P. BERGHEI) [#1]","MULTIPLE SECRETED INVASION-RELATED PROTEINS BY IP-MS (P. BERGHEI) [#1]"],"other_free_text":["Loss-of-function reduces gliding motility, invasion, and egress in T. gondii and P. berghei [#0]","Antibodies against the P. berghei ortholog inhibit erythrocyte invasion in murine models [#1]","P. falciparum role is a structural/dimensional inference only; no direct experiment on PF3D7_1361800 [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"27978434","id":"PMC_27978434","title":"An Apicomplexan Actin-Binding Protein Serves as a Connector and Lipid Sensor to Coordinate Motility and Invasion.","date":"2016","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/27978434","citation_count":86,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GAC","glideosome-associated connector"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41152982","id":"","title":"The Plasmodium berghei merozoite protein PbGAC is critically involved in erythrocyte binding during invasion.","date":"2025","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/41152982","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GAC"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42001110","id":"","title":"Targeting protein-protein interactions in Plasmodium: from asexual replication to sexual development.","date":"2026","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/42001110","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GAC"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42253101","id":"","title":"Extracellular vesicles participate in proteostasis and heat shock adaptation in Plasmodium falciparum.","date":"2026","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/42253101","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GAC"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41716278","id":"","title":"Molecular mechanisms involved in Plasmodium gametocytogenesis.","date":"2026","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41716278","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GAC"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37988347","id":"","title":"Protein kinase PfPK2 mediated signalling is critical for host erythrocyte invasion by malaria parasite.","date":"2023","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/37988347","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GAC"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35377914","id":"","title":"High-resolution structures of malaria parasite actomyosin and actin filaments.","date":"2022","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/35377914","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GAC"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9880,"output_tokens":1222,"usd":0.023985,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6044,"output_tokens":2418,"usd":0.045335,"stage2_stop_reason":"end_turn"},"total_usd":0.06932,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"GAC (glideosome-associated connector) in Toxoplasma gondii and Plasmodium berghei binds to and stabilizes filamentous actin through its N-terminal armadillo domain, connects micronemal transmembrane adhesins (TgMIC2) to the actomyosin system, and localizes to the apical pole in invasive stages; its PH domain binds phosphatidic acid, a lipid mediator associated with microneme exocytosis. Apical positioning of TgGAC depends on the apical lysine methyltransferase TgAKMT. Loss-of-function experiments established roles in gliding motility, invasion, and egress.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, live imaging/IFA for localization, actin-binding assays, lipid-binding assays with PH domain, genetic knockdown/conditional knockout with phenotypic readout (gliding motility, invasion, egress)\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, actin-binding assay, lipid-binding assay, localization, functional knockdown) in a single rigorous study, with both T. gondii and P. berghei orthologs examined\",\n      \"pmids\": [\"27978434\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"P. berghei GAC (PbGAC; PbANKA_1137800) localizes predominantly to the extreme apical region of the merozoite, binds heparin and the erythrocyte surface in a heparan sulfate-dependent manner, and interacts by immunoprecipitation/mass spectrometry with multiple secreted proteins involved in erythrocyte invasion. Antibodies against PbGAC inhibit invasion in murine models.\",\n      \"method\": \"Western blotting, immunofluorescence, flow cytometry, heparinase II treatment (heparan sulfate-binding assay), heparin-sepharose pulldown, immunoprecipitation followed by global mass spectrometry, passive immunization invasion inhibition assay\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (binding assays, IP-MS, functional inhibition) in a single lab study; replication not yet established\",\n      \"pmids\": [\"41152982\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"ANKA\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structural analysis of the P. falciparum glideosome complex indicates that GAC (with a Dmax ~25 nm in solution) physically links actin filaments to the plasma membrane and imposes significant geometric/steric constraints on the arrangement of the actomyosin motor within the sub-pellicular compartment (~30 nm between IMC and plasma membrane).\",\n      \"method\": \"Cryo-EM structural determination of PfActomyosin complex; structural modeling of GAC dimensions cited from prior biophysical data\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — structural inference about GAC's role is derived from modeling/dimensional considerations in a paper primarily characterizing PfMyoA:PfAct1; no direct experiment on GAC itself was performed in this study\",\n      \"pmids\": [\"35377914\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"GAC (PF3D7_1361800) is a conserved armadillo/PH domain-containing apical connector protein that stabilizes filamentous actin via its N-terminal domain, binds the cytoplasmic tails of micronemal transmembrane adhesins (e.g., MTRAP/MIC2), and anchors to the inner plasma membrane leaflet via phosphatidic acid recognition by its PH domain, thereby physically coupling extracellular adhesion to the intracellular actomyosin motor to power gliding motility, host cell invasion, and egress; in P. berghei, GAC additionally engages heparan sulfate proteoglycans on the erythrocyte surface and interacts with multiple invasion-related secreted proteins at the merozoite apical tip.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GAC (PF3D7_1361800) is a conserved apical connector protein of apicomplexan invasive stages that physically couples extracellular adhesion to the intracellular actomyosin motor to drive gliding motility, host cell invasion, and egress [#0]. Characterized in the Toxoplasma gondii and Plasmodium berghei orthologs, GAC binds and stabilizes filamentous actin through its N-terminal armadillo domain, engages the cytoplasmic tail of the micronemal transmembrane adhesin TgMIC2, and anchors to membranes through PH-domain recognition of phosphatidic acid, with its apical positioning depending on the lysine methyltransferase TgAKMT [#0]. In P. berghei, the ortholog concentrates at the extreme apical tip of the merozoite, binds the erythrocyte surface in a heparan sulfate-dependent manner, associates by IP-MS with multiple secreted invasion proteins, and is a target of invasion-inhibitory antibodies [#1]. No direct experimental characterization of the P. falciparum PF3D7_1361800 protein itself is present in the corpus beyond a structural inference that it bridges actin filaments to the plasma membrane within the geometrically constrained sub-pellicular compartment [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the founding molecular function of GAC: how does extracellular adhesion transmit force to the intracellular motor? GAC was shown to be the physical bridge linking micronemal adhesins to actomyosin.\",\n      \"evidence\": \"Co-IP, actin- and lipid-binding assays, localization, and conditional knockout with gliding/invasion/egress readouts in T. gondii and P. berghei\",\n      \"pmids\": [\"27978434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct experiment on the P. falciparum PF3D7_1361800 ortholog\",\n        \"Structural basis of simultaneous actin, adhesin-tail, and phosphatidic acid engagement not resolved\",\n        \"Mechanism by which TgAKMT controls apical positioning undefined\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Addressed how GAC fits within the crowded sub-pellicular space: structural modeling of the P. falciparum glideosome inferred that GAC's elongated dimensions bridge actin to the plasma membrane and constrain motor geometry.\",\n      \"evidence\": \"Cryo-EM of the PfActomyosin complex with dimensional modeling of GAC cited from prior biophysical data; no direct experiment on GAC performed\",\n      \"pmids\": [\"35377914\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Inference only \\u2014 no direct structural or functional experiment on PF3D7_1361800 was performed in this study\",\n        \"GAC's geometry within the assembled glideosome not directly visualized\",\n        \"Whether P. falciparum GAC behaves as the orthologs do is not tested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended GAC's role beyond the intracellular motor connector: does GAC also directly contact the host cell? The P. berghei ortholog was shown to bind the erythrocyte surface via heparan sulfate and to be an invasion-inhibitory antibody target.\",\n      \"evidence\": \"Western blot, IFA, flow cytometry, heparinase II and heparin-sepharose binding assays, IP-MS, and passive immunization invasion-inhibition in murine models\",\n      \"pmids\": [\"41152982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; replication not yet established\",\n        \"Direct host-parasite binding partner of GAC on the erythrocyte not identified\",\n        \"Whether apparent apical-surface exposure reflects genuine extracellular display versus co-purified secreted proteins is unresolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"ANKA\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the P. falciparum PF3D7_1361800 protein directly recapitulates the actin-binding, adhesin-linking, and lipid-anchoring activities defined in orthologs, and whether it engages host-cell ligands, remains experimentally unaddressed in this corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical or genetic characterization of PF3D7_1361800 itself\",\n        \"No structural model of the P. falciparum protein\",\n        \"Host-cell binding shown only for the P. berghei ortholog\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051015\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005543\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020009\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0071693\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0006909\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"Glideosome / actomyosin motor complex (as connector) [#0, #2]\"\n    ],\n    \"partners\": [\n      \"Filamentous actin (F-actin) via N-terminal armadillo domain [#0]\",\n      \"TgMIC2 micronemal adhesin cytoplasmic tail [#0]\",\n      \"Phosphatidic acid (PH domain) [#0]\",\n      \"TgAKMT (apical lysine methyltransferase, controls apical positioning) [#0]\",\n      \"Heparan sulfate / heparin on the erythrocyte surface (P. berghei) [#1]\",\n      \"Multiple secreted invasion-related proteins by IP-MS (P. berghei) [#1]\"\n    ],\n    \"other_free_text\": [\n      \"Loss-of-function reduces gliding motility, invasion, and egress in T. gondii and P. berghei [#0]\",\n      \"Antibodies against the P. berghei ortholog inhibit erythrocyte invasion in murine models [#1]\",\n      \"P. falciparum role is a structural/dimensional inference only; no direct experiment on PF3D7_1361800 [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1361800","name":null,"product":"glideosome-associated connector","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1137800","name":null,"product":"glideosome-associated connector","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1109500","name":null,"product":"glideosome-associated connector, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"GAC","evaluation":null}