{"gene":"PF3D7_1436800","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2010,"finding":"ClpR (PfClpR) was identified as an inactive version of the ClpP protease subunit in P. falciparum. Both PfClpP and PfClpR form mostly homoheptameric rings, as demonstrated by size-exclusion chromatography, analytical ultracentrifugation, and electron microscopy. The data suggest the presence of a ClpCRP complex in the apicoplast.","method":"Size-exclusion chromatography, analytical ultracentrifugation, electron microscopy","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biophysical methods (SEC, AUC, EM) from a single lab establishing quaternary structure and apicoplast localization","pmids":["20887733"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"ClpR (PfClpR) was localized to the apicoplast of P. falciparum, as determined by expression data and subcellular localization experiments in blood-stage parasites.","method":"Subcellular localization (immunofluorescence/fractionation, consistent with apicoplast marker)","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with multiple supporting methods in a single lab study","pmids":["20887733"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"The X-ray crystal structure of PfClpR heptamer was solved, revealing that the PfClpR monomer adopts a fold similar to ClpP but contains a unique 'R-motif' (a β-turn) located near the inactive catalytic triad. The PfClpR heptamer displays a more open and flat ring compared to a ClpP heptamer. Biochemical and structural data demonstrated that, contrary to observations in other organisms, PfClpP and PfClpR do NOT form a stable heterocomplex in the apicoplast of P. falciparum.","method":"X-ray crystallography, biochemical interaction assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray crystal structure of PfClpR with active-site analysis and R-motif identification, complemented by biochemical heterocomplex interaction data; two independent labs (El Bakkouri/Houry and Mohmmed groups) contributed","pmids":["23192353"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"PfClpR was confirmed to be localized in the P. falciparum apicoplast, consistent with earlier data, and is structurally an inactive (non-catalytic) paralog of ClpP due to an altered catalytic triad region.","method":"X-ray crystallography (structural inference of catalytic inactivity), apicoplast localization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination directly shows absence of functional catalytic triad, combined with direct localization; replicates finding from PMID:20887733","pmids":["23192353"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfClpR (PF3D7_1436800) is an apicoplast-localized, catalytically inactive paralog of ClpP that forms homoheptameric rings with a unique structural 'R-motif' near its non-functional catalytic triad; unlike its orthologs in other organisms, PfClpR does not form a stable heterocomplex with PfClpP in P. falciparum."},"narrative":{"mechanistic_narrative":"ClpR (PF3D7_1436800) is a catalytically inactive paralog of the ClpP protease subunit that localizes to the apicoplast of blood-stage P. falciparum [PMID:20887733, PMID:23192353]. Like PfClpP, ClpR assembles predominantly into homoheptameric rings, as shown by size-exclusion chromatography, analytical ultracentrifugation, and electron microscopy [PMID:20887733]. The X-ray crystal structure shows that the ClpR monomer adopts a ClpP-like fold but carries a unique 'R-motif' β-turn near an altered, non-functional catalytic triad, and its heptamer forms a more open, flat ring than a ClpP heptamer [PMID:23192353]. In contrast to Clp orthologs in other organisms, ClpR and PfClpP do not form a stable heterocomplex in the P. falciparum apicoplast [PMID:23192353], though the original characterization proposed the existence of a ClpCRP complex [PMID:20887733]. Beyond its structural characterization, localization, and non-functional catalytic status, no substrate, enzymatic activity, or defined complex role for ClpR has been characterized in the available corpus.","teleology":[{"year":2010,"claim":"Establishing whether P. falciparum encodes a Clp proteolytic component and where it acts required identifying ClpR as an inactive ClpP paralog that forms homoheptameric rings and resides in the apicoplast.","evidence":"Size-exclusion chromatography, analytical ultracentrifugation, and electron microscopy of PfClpR, with subcellular localization in blood-stage parasites","pmids":["20887733"],"confidence":"Medium","gaps":["The proposed ClpCRP complex was inferred, not directly reconstituted","No substrate or physiological function of ClpR was defined","Whether ClpR contributes any regulatory or scaffolding role was not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Determining the structural basis of ClpR's catalytic inactivity and its interaction behavior showed a ClpP-like fold with a unique R-motif near a non-functional triad and, unexpectedly, no stable heterocomplex with PfClpP.","evidence":"X-ray crystallography of the PfClpR heptamer plus biochemical interaction assays and apicoplast localization","pmids":["23192353"],"confidence":"High","gaps":["The functional purpose of the open, flat heptameric ring is unknown","Absence of a stable PfClpP-PfClpR heterocomplex leaves ClpR's operational partner undefined","No proteolytic substrate or in vivo role established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"What functional role ClpR plays given its catalytic inactivity and its failure to form a stable complex with PfClpP remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No physiological substrate or binding partner for ClpR has been identified","The in vivo consequence of ClpR loss or the essentiality of ClpR has not been characterized","How the R-motif and open ring architecture contribute to apicoplast Clp machinery function is unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Homoheptameric ClpR ring [#0]","Proposed ClpCRP complex (inferred, not stably reconstituted) [#0]"],"partners":[],"other_free_text":["ClpR is a catalytically inactive paralog of ClpP with an altered, non-functional catalytic triad [#2, #3]","ClpR monomer adopts a ClpP-like fold with a unique 'R-motif' β-turn near the inactive triad; its heptamer forms a more open, flat ring than a ClpP heptamer [#2]","In P. falciparum, ClpR does not form a stable heterocomplex with PfClpP, contrary to Clp orthologs in other organisms [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"20887733","id":"PMC_20887733","title":"The Clp chaperones and proteases of the human malaria parasite Plasmodium falciparum.","date":"2010","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20887733","citation_count":71,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfClpR"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33497624","id":"PMC_33497624","title":"Structure, function, and substrates of Clp AAA+ protease systems in cyanobacteria, plastids, and apicoplasts: A comparative analysis.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33497624","citation_count":61,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ATP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20545854","id":"PMC_20545854","title":"A cyanobacterial serine protease of Plasmodium falciparum is targeted to the apicoplast and plays an important role in its growth and development.","date":"2010","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20545854","citation_count":36,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ATP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23192353","id":"PMC_23192353","title":"Structural insights into the inactive subunit of the apicoplast-localized caseinolytic protease complex of Plasmodium falciparum.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23192353","citation_count":23,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ClpR","PfClpR"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4927,"output_tokens":1127,"usd":0.015843,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5939,"output_tokens":1676,"usd":0.035798,"stage2_stop_reason":"end_turn"},"total_usd":0.051641,"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\": 2010,\n      \"finding\": \"ClpR (PfClpR) was identified as an inactive version of the ClpP protease subunit in P. falciparum. Both PfClpP and PfClpR form mostly homoheptameric rings, as demonstrated by size-exclusion chromatography, analytical ultracentrifugation, and electron microscopy. The data suggest the presence of a ClpCRP complex in the apicoplast.\",\n      \"method\": \"Size-exclusion chromatography, analytical ultracentrifugation, electron microscopy\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biophysical methods (SEC, AUC, EM) from a single lab establishing quaternary structure and apicoplast localization\",\n      \"pmids\": [\"20887733\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ClpR (PfClpR) was localized to the apicoplast of P. falciparum, as determined by expression data and subcellular localization experiments in blood-stage parasites.\",\n      \"method\": \"Subcellular localization (immunofluorescence/fractionation, consistent with apicoplast marker)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with multiple supporting methods in a single lab study\",\n      \"pmids\": [\"20887733\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The X-ray crystal structure of PfClpR heptamer was solved, revealing that the PfClpR monomer adopts a fold similar to ClpP but contains a unique 'R-motif' (a β-turn) located near the inactive catalytic triad. The PfClpR heptamer displays a more open and flat ring compared to a ClpP heptamer. Biochemical and structural data demonstrated that, contrary to observations in other organisms, PfClpP and PfClpR do NOT form a stable heterocomplex in the apicoplast of P. falciparum.\",\n      \"method\": \"X-ray crystallography, biochemical interaction assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray crystal structure of PfClpR with active-site analysis and R-motif identification, complemented by biochemical heterocomplex interaction data; two independent labs (El Bakkouri/Houry and Mohmmed groups) contributed\",\n      \"pmids\": [\"23192353\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PfClpR was confirmed to be localized in the P. falciparum apicoplast, consistent with earlier data, and is structurally an inactive (non-catalytic) paralog of ClpP due to an altered catalytic triad region.\",\n      \"method\": \"X-ray crystallography (structural inference of catalytic inactivity), apicoplast localization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination directly shows absence of functional catalytic triad, combined with direct localization; replicates finding from PMID:20887733\",\n      \"pmids\": [\"23192353\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfClpR (PF3D7_1436800) is an apicoplast-localized, catalytically inactive paralog of ClpP that forms homoheptameric rings with a unique structural 'R-motif' near its non-functional catalytic triad; unlike its orthologs in other organisms, PfClpR does not form a stable heterocomplex with PfClpP in P. falciparum.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ClpR (PF3D7_1436800) is a catalytically inactive paralog of the ClpP protease subunit that localizes to the apicoplast of blood-stage P. falciparum [#0, #1, #3]. Like PfClpP, ClpR assembles predominantly into homoheptameric rings, as shown by size-exclusion chromatography, analytical ultracentrifugation, and electron microscopy [#0]. The X-ray crystal structure shows that the ClpR monomer adopts a ClpP-like fold but carries a unique 'R-motif' β-turn near an altered, non-functional catalytic triad, and its heptamer forms a more open, flat ring than a ClpP heptamer [#2, #3]. In contrast to Clp orthologs in other organisms, ClpR and PfClpP do not form a stable heterocomplex in the P. falciparum apicoplast [#2], though the original characterization proposed the existence of a ClpCRP complex [#0]. Beyond its structural characterization, localization, and non-functional catalytic status, no substrate, enzymatic activity, or defined complex role for ClpR has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing whether P. falciparum encodes a Clp proteolytic component and where it acts required identifying ClpR as an inactive ClpP paralog that forms homoheptameric rings and resides in the apicoplast.\",\n      \"evidence\": \"Size-exclusion chromatography, analytical ultracentrifugation, and electron microscopy of PfClpR, with subcellular localization in blood-stage parasites\",\n      \"pmids\": [\n        \"20887733\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The proposed ClpCRP complex was inferred, not directly reconstituted\",\n        \"No substrate or physiological function of ClpR was defined\",\n        \"Whether ClpR contributes any regulatory or scaffolding role was not addressed\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Determining the structural basis of ClpR's catalytic inactivity and its interaction behavior showed a ClpP-like fold with a unique R-motif near a non-functional triad and, unexpectedly, no stable heterocomplex with PfClpP.\",\n      \"evidence\": \"X-ray crystallography of the PfClpR heptamer plus biochemical interaction assays and apicoplast localization\",\n      \"pmids\": [\n        \"23192353\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The functional purpose of the open, flat heptameric ring is unknown\",\n        \"Absence of a stable PfClpP-PfClpR heterocomplex leaves ClpR's operational partner undefined\",\n        \"No proteolytic substrate or in vivo role established\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What functional role ClpR plays given its catalytic inactivity and its failure to form a stable complex with PfClpP remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No physiological substrate or binding partner for ClpR has been identified\",\n        \"The in vivo consequence of ClpR loss or the essentiality of ClpR has not been characterized\",\n        \"How the R-motif and open ring architecture contribute to apicoplast Clp machinery function is unknown\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\n        \"term_id\": \"apicoplast\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          3\n        ]\n      }\n    ],\n    \"pathway\": [],\n    \"complexes\": [\n      \"Homoheptameric ClpR ring [#0]\",\n      \"Proposed ClpCRP complex (inferred, not stably reconstituted) [#0]\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"ClpR is a catalytically inactive paralog of ClpP with an altered, non-functional catalytic triad [#2, #3]\",\n      \"ClpR monomer adopts a ClpP-like fold with a unique 'R-motif' β-turn near the inactive triad; its heptamer forms a more open, flat ring than a ClpP heptamer [#2]\",\n      \"In P. falciparum, ClpR does not form a stable heterocomplex with PfClpP, contrary to Clp orthologs in other organisms [#2]\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1436800","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_0816600, PF3D7_1116800). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1436800","name":null,"product":"ATP-dependent Clp protease proteolytic subunit","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0612000","name":null,"product":"ATP-dependent Clp protease proteolytic subunit, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0423400","name":null,"product":"ATP-dependent Clp protease proteolytic subunit, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ClpR","evaluation":null}