{"gene":"PF3D7_1405400","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2025,"finding":"PF3D7_1405400 (PfMutS), a mismatch repair protein carrying an additional endonuclease domain, was localized to the mitochondrion of P. falciparum by immunofluorescence using antibodies against recombinant protein, and was shown to interact with PfExomit2 (a mitochondrial exonuclease) in pull-down assays, placing PfMutS in the mitochondrial MMR pathway.","method":"Immunofluorescence localization with anti-recombinant-protein antibodies; pull-down (co-purification) assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization experiment with functional consequence (mitochondrial MMR pathway placement) and pull-down interaction, single lab, two orthogonal methods","pmids":["41243319"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"Point mutations in MutS (PF3D7_1405400) and 17 other DNA repair genes were identified by genome sequencing in P. falciparum mutator strains Dd2 and W2, which fail to induce DNA repair transcriptional responses upon MMS-induced DNA damage, consistent with MutS contributing to the DNA damage response in these strains.","method":"Genome sequencing of mutator strains; transcriptional profiling after MMS treatment","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genomic/transcriptomic evidence only, no direct functional assay of MutS specifically; single lab, single approach","pmids":["27033103"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2"},{"species":"Plasmodium falciparum","strain":"W2"}]}],"current_model":"PF3D7_1405400 (MutS/PfMutS) is a mismatch repair protein bearing an additional endonuclease domain that localizes to the mitochondrion of P. falciparum and physically interacts with the mitochondrial exonuclease PfExomit2, implicating it in mitochondrial MMR; point mutations in its coding sequence are associated with a mutator phenotype and failure to induce DNA repair responses in drug-resistant strains."},"narrative":{"mechanistic_narrative":"PF3D7_1405400 (MutS/PfMutS) is a putative DNA mismatch repair protein of Plasmodium falciparum that carries an additional endonuclease domain and functions in the mitochondrial MMR pathway [PMID:41243319]. It localizes to the mitochondrion and physically associates with the mitochondrial exonuclease PfExomit2, placing it within a mitochondrial mismatch-repair machinery [PMID:41243319]. Beyond this localization and interaction, the enzymatic activity and repair mechanism of PF3D7_1405400 have not been directly characterized in the available corpus.","teleology":[{"year":2016,"claim":"Before this work it was unknown whether MutS contributed to the DNA damage response in P. falciparum; genome sequencing of mutator strains linked point mutations in MutS to a defective repair response, implicating it in genome maintenance.","evidence":"Genome sequencing of mutator strains Dd2 and W2 with transcriptional profiling after MMS-induced DNA damage","pmids":["27033103"],"confidence":"Low","gaps":["Genomic/transcriptomic correlation only; no direct functional assay isolating MutS activity","Mutations were identified alongside 17 other DNA repair genes, so MutS-specific causality is not established","Does not localize the protein or define its repair mechanism"],"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2"},{"species":"Plasmodium falciparum","strain":"W2"}]},{"year":2025,"claim":"The subcellular compartment and physical partners of PfMutS were unresolved; immunofluorescence and pull-down assays localized it to the mitochondrion and identified its interaction with PfExomit2, establishing PfMutS as a component of a mitochondrial MMR pathway.","evidence":"Immunofluorescence localization with anti-recombinant-protein antibodies and pull-down (co-purification) assay in P. falciparum","pmids":["41243319"],"confidence":"Medium","gaps":["Interaction shown by pull-down without reciprocal validation or reconstitution","The catalytic activity of the endonuclease domain has not been demonstrated biochemically","The functional consequence of the PfMutS-PfExomit2 interaction for mitochondrial repair was not directly tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether the endonuclease domain of PF3D7_1405400 is catalytically active and how PfMutS mechanistically executes mismatch recognition and repair in the mitochondrion remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro reconstitution of mismatch recognition or repair activity","No structural model of the protein or its endonuclease domain","No genetic knockout/knockdown phenotype directly attributed to PF3D7_1405400"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFEXOMIT2 (MITOCHONDRIAL EXONUCLEASE)"],"other_free_text":["Carries an additional endonuclease domain [#0]","Point mutations associated with a mutator phenotype and failure to induce DNA repair transcriptional responses in P. falciparum strains Dd2 and W2 [#1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"27033103","id":"PMC_27033103","title":"DNA damage regulation and its role in drug-related phenotypes in the malaria parasites.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27033103","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15948708","id":"PMC_15948708","title":"DNA-[adenine] methylation in lower eukaryotes.","date":"2005","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/15948708","citation_count":42,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"2892060","id":"PMC_2892060","title":"From Laveran's discovery to DNA probes: new trends in diagnosis of malaria.","date":"1987","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/2892060","citation_count":31,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41243319","id":"PMC_41243319","title":"Plasmodium mitochondrial exodeoxyribonucleases, Exomit1 and Exomit2, are conserved within alveolates with Exomit1 essential for the establishment of blood-stage infection.","date":"2025","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/41243319","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfMutS"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4373,"output_tokens":702,"usd":0.011824,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5306,"output_tokens":1462,"usd":0.03154,"stage2_stop_reason":"end_turn"},"total_usd":0.043364,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"PF3D7_1405400 (PfMutS), a mismatch repair protein carrying an additional endonuclease domain, was localized to the mitochondrion of P. falciparum by immunofluorescence using antibodies against recombinant protein, and was shown to interact with PfExomit2 (a mitochondrial exonuclease) in pull-down assays, placing PfMutS in the mitochondrial MMR pathway.\",\n      \"method\": \"Immunofluorescence localization with anti-recombinant-protein antibodies; pull-down (co-purification) assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization experiment with functional consequence (mitochondrial MMR pathway placement) and pull-down interaction, single lab, two orthogonal methods\",\n      \"pmids\": [\"41243319\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Point mutations in MutS (PF3D7_1405400) and 17 other DNA repair genes were identified by genome sequencing in P. falciparum mutator strains Dd2 and W2, which fail to induce DNA repair transcriptional responses upon MMS-induced DNA damage, consistent with MutS contributing to the DNA damage response in these strains.\",\n      \"method\": \"Genome sequencing of mutator strains; transcriptional profiling after MMS treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genomic/transcriptomic evidence only, no direct functional assay of MutS specifically; single lab, single approach\",\n      \"pmids\": [\"27033103\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"W2\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1405400 (MutS/PfMutS) is a mismatch repair protein bearing an additional endonuclease domain that localizes to the mitochondrion of P. falciparum and physically interacts with the mitochondrial exonuclease PfExomit2, implicating it in mitochondrial MMR; point mutations in its coding sequence are associated with a mutator phenotype and failure to induce DNA repair responses in drug-resistant strains.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1405400 (MutS/PfMutS) is a putative DNA mismatch repair protein of Plasmodium falciparum that carries an additional endonuclease domain and functions in the mitochondrial MMR pathway [#0]. It localizes to the mitochondrion and physically associates with the mitochondrial exonuclease PfExomit2, placing it within a mitochondrial mismatch-repair machinery [#0]. Beyond this localization and interaction, the enzymatic activity and repair mechanism of PF3D7_1405400 have not been directly characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Before this work it was unknown whether MutS contributed to the DNA damage response in P. falciparum; genome sequencing of mutator strains linked point mutations in MutS to a defective repair response, implicating it in genome maintenance.\",\n      \"evidence\": \"Genome sequencing of mutator strains Dd2 and W2 with transcriptional profiling after MMS-induced DNA damage\",\n      \"pmids\": [\"27033103\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Genomic/transcriptomic correlation only; no direct functional assay isolating MutS activity\",\n        \"Mutations were identified alongside 17 other DNA repair genes, so MutS-specific causality is not established\",\n        \"Does not localize the protein or define its repair mechanism\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"W2\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The subcellular compartment and physical partners of PfMutS were unresolved; immunofluorescence and pull-down assays localized it to the mitochondrion and identified its interaction with PfExomit2, establishing PfMutS as a component of a mitochondrial MMR pathway.\",\n      \"evidence\": \"Immunofluorescence localization with anti-recombinant-protein antibodies and pull-down (co-purification) assay in P. falciparum\",\n      \"pmids\": [\"41243319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction shown by pull-down without reciprocal validation or reconstitution\",\n        \"The catalytic activity of the endonuclease domain has not been demonstrated biochemically\",\n        \"The functional consequence of the PfMutS-PfExomit2 interaction for mitochondrial repair was not directly tested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the endonuclease domain of PF3D7_1405400 is catalytically active and how PfMutS mechanistically executes mismatch recognition and repair in the mitochondrion remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of mismatch recognition or repair activity\",\n        \"No structural model of the protein or its endonuclease domain\",\n        \"No genetic knockout/knockdown phenotype directly attributed to PF3D7_1405400\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030983\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006298\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PfExomit2 (mitochondrial exonuclease)\"],\n    \"other_free_text\": [\n      \"Carries an additional endonuclease domain [#0]\",\n      \"Point mutations associated with a mutator phenotype and failure to induce DNA repair transcriptional responses in P. falciparum strains Dd2 and W2 [#1]\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1405400","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 1 of 2 cited papers name other catalogue genes (PF3D7_1107400). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1405400","name":null,"product":"DNA mismatch repair protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1036800","name":null,"product":"DNA mismatch repair protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1352700","name":null,"product":"DNA mismatch repair protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"MutS","evaluation":null}