{"gene":"PF3D7_1311000","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2013,"finding":"ISD11 (as the effector/partner of IscS) localizes exclusively to the mitochondrion in P. falciparum, establishing that the Isc pathway (including ISD11) cannot contribute to apicoplast Fe-S cluster synthesis.","method":"Subcellular fractionation / localization experiments establishing mitochondrial-only localization of IscS and its effector ISD11","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional inference, single lab but with complementary pathway disruption experiments","pmids":["24086138"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"ISD11 forms a cysteine desulfurase complex with PfIscS (PfIscS-PfIsd11), and this complex assembles around a PfIscS tetramer (rather than the canonical dimer found in other organisms), yielding a symmetric hetero-hexamer [2×(2PfIscS-2PfIsd11-2PfIscU)] with the scaffold protein PfIscU.","method":"Small angle X-ray scattering (SAXS), spectral studies, and biochemical reconstitution of the complex","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SAXS structural analysis combined with biochemical reconstitution in a single focused study establishing the unique quaternary structure","pmids":["34032321"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"Plasmodium falciparum mitochondrial ACP (mACP) binds and stabilizes the ISD11-Nfs1 complex required for Fe-S cluster biosynthesis, despite lacking the 4-phosphopantetheine (Ppant) group that mediates this association in other eukaryotes; knockdown of mACP causes loss of Nfs1 and the Rieske Fe-S protein in ETC complex III.","method":"Biochemical pulldown/binding studies, ligand-dependent knockdown of mACP with phenotypic readout (loss of Nfs1 and Rieske Fe-S protein assessed by western blot/MS)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus conditional knockdown with multiple orthogonal phenotypic readouts in a single rigorous study","pmids":["34612205"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"In P. falciparum, ISD11 is a mitochondria-localized component of the ISC Fe-S cluster biogenesis pathway that forms a cysteine desulfurase sub-complex with PfIscS and the scaffold PfIscU in an unusual hetero-hexameric arrangement (built around a PfIscS tetramer rather than the canonical dimer), and is stabilized by an interaction with mitochondrial ACP (mACP) that is independent of the Ppant prosthetic group normally required for this association in other eukaryotes."},"narrative":{"mechanistic_narrative":"ISD11 (PF3D7_1311000) is a mitochondrion-localized component of the ISC iron-sulfur cluster biogenesis pathway in P. falciparum, restricted exclusively to the mitochondrion so that the Isc pathway cannot contribute to apicoplast Fe-S cluster synthesis [PMID:24086138]. It partners with the cysteine desulfurase PfIscS to form a PfIscS-PfIsd11 complex that, together with the scaffold protein PfIscU, assembles into an unusual symmetric hetero-hexamer [2×(2PfIscS-2PfIsd11-2PfIscU)] built around a PfIscS tetramer rather than the canonical dimer seen in other organisms [PMID:34032321]. The ISD11-Nfs1 (PfIscS) complex is bound and stabilized by mitochondrial ACP (mACP), an association that occurs despite the absence of the 4-phosphopantetheine group that mediates this interaction in other eukaryotes; loss of mACP destabilizes Nfs1 and the downstream Rieske Fe-S protein of ETC complex III [PMID:34612205]. Beyond these findings, no further mechanistic detail specific to ISD11 has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"It was unknown which compartment the Plasmodium Isc pathway serves; localizing ISD11 with IscS to the mitochondrion established that this Fe-S biogenesis machinery is mitochondrial and cannot supply the apicoplast.","evidence":"Subcellular fractionation/localization of IscS and its effector ISD11 in P. falciparum","pmids":["24086138"],"confidence":"Medium","gaps":["Does not resolve ISD11's own molecular role within the complex versus IscS","No quantitative import or topology data for ISD11 specifically"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"The quaternary organization of the desulfurase machinery was undefined; structural and biochemical reconstitution showed ISD11 partners with PfIscS and PfIscU in a hetero-hexamer built on a PfIscS tetramer, revealing a non-canonical assembly.","evidence":"SAXS, spectral studies and biochemical reconstitution of the PfIscS-PfIsd11-PfIscU complex","pmids":["34032321"],"confidence":"High","gaps":["The specific contribution of ISD11 to the tetrameric arrangement is not isolated","No high-resolution structure of ISD11 within the complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"How the ISD11-containing desulfurase complex is stabilized was unknown; mACP was shown to bind and stabilize the ISD11-Nfs1 complex in a Ppant-independent manner, linking Fe-S biogenesis to downstream ETC complex III integrity.","evidence":"Binding/pulldown assays and ligand-dependent mACP knockdown with loss of Nfs1 and Rieske Fe-S protein readouts","pmids":["34612205"],"confidence":"High","gaps":["The direct ISD11-mACP interaction interface is not mapped","Whether mACP loss destabilizes ISD11 itself is not directly reported"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The precise molecular function ISD11 contributes to cysteine desulfurase activity, its essentiality, and how its non-canonical assembly and mACP dependence affect parasite Fe-S output remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No conditional knockdown or knockout of ISD11 itself in the corpus","No high-resolution structure of ISD11","Functional consequence of the tetramer-based assembly for cluster synthesis untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PfIscS-PfIsd11-PfIscU hetero-hexamer [2×(2PfIscS-2PfIsd11-2PfIscU)]","ISD11-Nfs1 (PfIscS) cysteine desulfurase complex"],"partners":["PFISCS (NFS1) CYSTEINE DESULFURASE","PFISCU SCAFFOLD PROTEIN","MITOCHONDRIAL ACP (MACP)"],"other_free_text":["Assembly built around a PfIscS tetramer rather than the canonical dimer [#1]","mACP stabilization of the ISD11-Nfs1 complex is independent of the 4-phosphopantetheine group [#2]","mACP knockdown causes loss of Nfs1 and the Rieske Fe-S protein of ETC complex III [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"16774588","id":"PMC_16774588","title":"Metabolic maps and functions of the Plasmodium mitochondrion.","date":"2006","source":"FEMS microbiology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/16774588","citation_count":206,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24086138","id":"PMC_24086138","title":"The suf iron-sulfur cluster synthesis pathway is required for apicoplast maintenance in malaria parasites.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24086138","citation_count":92,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ISD11"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34612205","id":"PMC_34612205","title":"Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34612205","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ISD11"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34032321","id":"PMC_34032321","title":"[Fe-S] biogenesis and unusual assembly of the ISC scaffold complex in the Plasmodium falciparum mitochondrion.","date":"2021","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34032321","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfISD11"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4767,"output_tokens":934,"usd":0.014155,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5667,"output_tokens":1976,"usd":0.038867,"stage2_stop_reason":"end_turn"},"total_usd":0.053022,"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\": 2013,\n      \"finding\": \"ISD11 (as the effector/partner of IscS) localizes exclusively to the mitochondrion in P. falciparum, establishing that the Isc pathway (including ISD11) cannot contribute to apicoplast Fe-S cluster synthesis.\",\n      \"method\": \"Subcellular fractionation / localization experiments establishing mitochondrial-only localization of IscS and its effector ISD11\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional inference, single lab but with complementary pathway disruption experiments\",\n      \"pmids\": [\"24086138\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ISD11 forms a cysteine desulfurase complex with PfIscS (PfIscS-PfIsd11), and this complex assembles around a PfIscS tetramer (rather than the canonical dimer found in other organisms), yielding a symmetric hetero-hexamer [2×(2PfIscS-2PfIsd11-2PfIscU)] with the scaffold protein PfIscU.\",\n      \"method\": \"Small angle X-ray scattering (SAXS), spectral studies, and biochemical reconstitution of the complex\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SAXS structural analysis combined with biochemical reconstitution in a single focused study establishing the unique quaternary structure\",\n      \"pmids\": [\"34032321\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plasmodium falciparum mitochondrial ACP (mACP) binds and stabilizes the ISD11-Nfs1 complex required for Fe-S cluster biosynthesis, despite lacking the 4-phosphopantetheine (Ppant) group that mediates this association in other eukaryotes; knockdown of mACP causes loss of Nfs1 and the Rieske Fe-S protein in ETC complex III.\",\n      \"method\": \"Biochemical pulldown/binding studies, ligand-dependent knockdown of mACP with phenotypic readout (loss of Nfs1 and Rieske Fe-S protein assessed by western blot/MS)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus conditional knockdown with multiple orthogonal phenotypic readouts in a single rigorous study\",\n      \"pmids\": [\"34612205\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"In P. falciparum, ISD11 is a mitochondria-localized component of the ISC Fe-S cluster biogenesis pathway that forms a cysteine desulfurase sub-complex with PfIscS and the scaffold PfIscU in an unusual hetero-hexameric arrangement (built around a PfIscS tetramer rather than the canonical dimer), and is stabilized by an interaction with mitochondrial ACP (mACP) that is independent of the Ppant prosthetic group normally required for this association in other eukaryotes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ISD11 (PF3D7_1311000) is a mitochondrion-localized component of the ISC iron-sulfur cluster biogenesis pathway in P. falciparum, restricted exclusively to the mitochondrion so that the Isc pathway cannot contribute to apicoplast Fe-S cluster synthesis [#0]. It partners with the cysteine desulfurase PfIscS to form a PfIscS-PfIsd11 complex that, together with the scaffold protein PfIscU, assembles into an unusual symmetric hetero-hexamer [2×(2PfIscS-2PfIsd11-2PfIscU)] built around a PfIscS tetramer rather than the canonical dimer seen in other organisms [#1]. The ISD11-Nfs1 (PfIscS) complex is bound and stabilized by mitochondrial ACP (mACP), an association that occurs despite the absence of the 4-phosphopantetheine group that mediates this interaction in other eukaryotes; loss of mACP destabilizes Nfs1 and the downstream Rieske Fe-S protein of ETC complex III [#2]. Beyond these findings, no further mechanistic detail specific to ISD11 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"It was unknown which compartment the Plasmodium Isc pathway serves; localizing ISD11 with IscS to the mitochondrion established that this Fe-S biogenesis machinery is mitochondrial and cannot supply the apicoplast.\",\n      \"evidence\": \"Subcellular fractionation/localization of IscS and its effector ISD11 in P. falciparum\",\n      \"pmids\": [\"24086138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve ISD11's own molecular role within the complex versus IscS\", \"No quantitative import or topology data for ISD11 specifically\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The quaternary organization of the desulfurase machinery was undefined; structural and biochemical reconstitution showed ISD11 partners with PfIscS and PfIscU in a hetero-hexamer built on a PfIscS tetramer, revealing a non-canonical assembly.\",\n      \"evidence\": \"SAXS, spectral studies and biochemical reconstitution of the PfIscS-PfIsd11-PfIscU complex\",\n      \"pmids\": [\"34032321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific contribution of ISD11 to the tetrameric arrangement is not isolated\", \"No high-resolution structure of ISD11 within the complex\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How the ISD11-containing desulfurase complex is stabilized was unknown; mACP was shown to bind and stabilize the ISD11-Nfs1 complex in a Ppant-independent manner, linking Fe-S biogenesis to downstream ETC complex III integrity.\",\n      \"evidence\": \"Binding/pulldown assays and ligand-dependent mACP knockdown with loss of Nfs1 and Rieske Fe-S protein readouts\",\n      \"pmids\": [\"34612205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The direct ISD11-mACP interaction interface is not mapped\", \"Whether mACP loss destabilizes ISD11 itself is not directly reported\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise molecular function ISD11 contributes to cysteine desulfurase activity, its essentiality, and how its non-canonical assembly and mACP dependence affect parasite Fe-S output remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No conditional knockdown or knockout of ISD11 itself in the corpus\", \"No high-resolution structure of ISD11\", \"Functional consequence of the tetramer-based assembly for cluster synthesis untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031071\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016226\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\n      \"PfIscS-PfIsd11-PfIscU hetero-hexamer [2×(2PfIscS-2PfIsd11-2PfIscU)]\",\n      \"ISD11-Nfs1 (PfIscS) cysteine desulfurase complex\"\n    ],\n    \"partners\": [\n      \"PfIscS (Nfs1) cysteine desulfurase\",\n      \"PfIscU scaffold protein\",\n      \"mitochondrial ACP (mACP)\"\n    ],\n    \"other_free_text\": [\n      \"Assembly built around a PfIscS tetramer rather than the canonical dimer [#1]\",\n      \"mACP stabilization of the ISD11-Nfs1 complex is independent of the 4-phosphopantetheine group [#2]\",\n      \"mACP knockdown causes loss of Nfs1 and the Rieske Fe-S protein of ETC complex III [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1311000","name":null,"product":"protein ISD11","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1409500","name":null,"product":"protein ISD11, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1411400","name":null,"product":"protein ISD11, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ISD11","evaluation":null}