{"gene":"PF3D7_0213100","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2015,"finding":"SIS1 (PFB0595w / PF3D7_0213100) localizes to the P. falciparum parasite cytosol, forms dimers, and recombinant SIS1 stimulates the in vitro ATPase activity of PfHsp70-1, consistent with a cochaperone function.","method":"Subcellular fractionation/localization, biochemical characterization of recombinant protein (dimerization assay), in vitro ATPase stimulation assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro ATPase assay and localization experiment from a single lab with two orthogonal methods (localization + biochemical activity)","pmids":["25701168"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"SIS1 (PF3D7_0213100) does NOT associate with the ribonucleotide reductase small subunit PfR2; the interaction of PfR2 with PfHsp70-1 is specific to the Type I cochaperone PfYdj1 (Pf3D7_1437900) and not to SIS1, a Type II cochaperone.","method":"Co-immunoprecipitation / interaction assay demonstrating specificity of PfR2 binding to PfYdj1 but not SIS1","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative result established by direct binding assay in a single lab; mechanistically informative for substrate specificity of SIS1 vs PfYdj1","pmids":["40938117"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]}],"current_model":"SIS1 (PF3D7_0213100) is a cytosolic, dimeric Type II J-domain protein (Hsp40 cochaperone) in P. falciparum that stimulates the ATPase activity of PfHsp70-1 in vitro, but does not associate with the ribonucleotide reductase subunit PfR2, demonstrating substrate selectivity distinct from the paralogous cochaperone PfYdj1."},"narrative":{"mechanistic_narrative":"SIS1 (PF3D7_0213100) is a cytosolic Type II J-domain cochaperone (Hsp40) of Plasmodium falciparum that functions as a partner to the major cytosolic chaperone PfHsp70-1 [PMID:25701168]. Recombinant SIS1 forms dimers and stimulates the in vitro ATPase activity of PfHsp70-1, the defining biochemical activity of a functional Hsp70 cochaperone [PMID:25701168]. SIS1 exhibits substrate selectivity that distinguishes it from the paralogous Type I cochaperone PfYdj1: SIS1 does not associate with the ribonucleotide reductase small subunit PfR2, whereas PfR2 recruitment to PfHsp70-1 is specific to PfYdj1 [PMID:40938117]. Beyond its cytosolic localization, PfHsp70-1 stimulation, and this negative substrate result, no further mechanistic detail — including physiological client proteins, structural basis of the J-domain interaction, or an in vivo phenotype — has been characterized for SIS1 in the available corpus.","teleology":[{"year":2015,"claim":"Establishing whether PF3D7_0213100 functions as a bona fide Hsp70 cochaperone required demonstrating both its cellular compartment and a direct effect on Hsp70 activity, which this work provided by placing SIS1 in the cytosol and showing it stimulates PfHsp70-1 ATPase turnover.","evidence":"Subcellular fractionation/localization plus in vitro ATPase stimulation and dimerization assays on recombinant SIS1","pmids":["25701168"],"confidence":"Medium","gaps":["No physiological client/substrate proteins identified","No structural characterization of the J-domain/PfHsp70-1 interaction","No in vivo essentiality or loss-of-function phenotype established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Whether SIS1 shares substrates with the paralogous cochaperone PfYdj1 was resolved by testing ribonucleotide reductase subunit PfR2, showing that PfR2 binds PfHsp70-1 via the Type I cochaperone PfYdj1 but not via the Type II cochaperone SIS1, establishing cochaperone substrate selectivity.","evidence":"Co-immunoprecipitation/interaction assays contrasting PfR2 binding to PfYdj1 versus SIS1 in P. falciparum 3D7","pmids":["40938117"],"confidence":"Medium","gaps":["Negative result establishes what SIS1 does not bind, but no positive SIS1-specific client was identified","Molecular basis for the differential selectivity between Type I and Type II cochaperones not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":null,"claim":"The physiological client repertoire of SIS1 and its role in parasite biology remain undefined.","evidence":"No discovery in the corpus identifies a SIS1-specific substrate or an in vivo function","pmids":[],"confidence":"Medium","gaps":["No positive SIS1 client protein identified","No genetic loss-of-function or essentiality data","No structural model of SIS1 or its Hsp70 engagement"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFHSP70-1 (STIMULATES ITS ATPASE ACTIVITY) [#0]","PFR2 RIBONUCLEOTIDE REDUCTASE SMALL SUBUNIT — DOES NOT ASSOCIATE WITH SIS1 [#1]"],"other_free_text":["SIS1 is a Type II J-domain protein (Hsp40 cochaperone), functionally distinguished from the Type I cochaperone PfYdj1 (PF3D7_1437900) by substrate selectivity [#1].","SIS1 forms dimers in vitro [#0]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25701168","id":"PMC_25701168","title":"PFB0595w is a Plasmodium falciparum J protein that co-localizes with PfHsp70-1 and can stimulate its in vitro ATP hydrolysis activity.","date":"2015","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25701168","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PFB0595w","SIS1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40938117","id":"PMC_40938117","title":"Inhibition of the assembly of Plasmodium Hsp70-1 and Hsp40 complex blocks DNA replication by destabilizing ribonucleotide reductase subunit-2.","date":"2025","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/40938117","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfSIS1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37457831","id":"","title":"The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery.","date":"2023","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/37457831","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SIS1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18093287","id":"","title":"Serial Analysis of Gene Expression in Plasmodium berghei salivary gland sporozoites.","date":"2007","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18093287","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SIS1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12620119","id":"","title":"Expression profiling of the schizont and trophozoite stages of Plasmodium falciparum with a long-oligonucleotide microarray.","date":"2003","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/12620119","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SIS1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7780,"output_tokens":687,"usd":0.016823,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5246,"output_tokens":1729,"usd":0.034728,"stage2_stop_reason":"end_turn"},"total_usd":0.051551,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"SIS1 (PFB0595w / PF3D7_0213100) localizes to the P. falciparum parasite cytosol, forms dimers, and recombinant SIS1 stimulates the in vitro ATPase activity of PfHsp70-1, consistent with a cochaperone function.\",\n      \"method\": \"Subcellular fractionation/localization, biochemical characterization of recombinant protein (dimerization assay), in vitro ATPase stimulation assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro ATPase assay and localization experiment from a single lab with two orthogonal methods (localization + biochemical activity)\",\n      \"pmids\": [\"25701168\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIS1 (PF3D7_0213100) does NOT associate with the ribonucleotide reductase small subunit PfR2; the interaction of PfR2 with PfHsp70-1 is specific to the Type I cochaperone PfYdj1 (Pf3D7_1437900) and not to SIS1, a Type II cochaperone.\",\n      \"method\": \"Co-immunoprecipitation / interaction assay demonstrating specificity of PfR2 binding to PfYdj1 but not SIS1\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative result established by direct binding assay in a single lab; mechanistically informative for substrate specificity of SIS1 vs PfYdj1\",\n      \"pmids\": [\"40938117\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}\n      ]\n    }\n  ],\n  \"current_model\": \"SIS1 (PF3D7_0213100) is a cytosolic, dimeric Type II J-domain protein (Hsp40 cochaperone) in P. falciparum that stimulates the ATPase activity of PfHsp70-1 in vitro, but does not associate with the ribonucleotide reductase subunit PfR2, demonstrating substrate selectivity distinct from the paralogous cochaperone PfYdj1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIS1 (PF3D7_0213100) is a cytosolic Type II J-domain cochaperone (Hsp40) of Plasmodium falciparum that functions as a partner to the major cytosolic chaperone PfHsp70-1 [#0]. Recombinant SIS1 forms dimers and stimulates the in vitro ATPase activity of PfHsp70-1, the defining biochemical activity of a functional Hsp70 cochaperone [#0]. SIS1 exhibits substrate selectivity that distinguishes it from the paralogous Type I cochaperone PfYdj1: SIS1 does not associate with the ribonucleotide reductase small subunit PfR2, whereas PfR2 recruitment to PfHsp70-1 is specific to PfYdj1 [#1]. Beyond its cytosolic localization, PfHsp70-1 stimulation, and this negative substrate result, no further mechanistic detail — including physiological client proteins, structural basis of the J-domain interaction, or an in vivo phenotype — has been characterized for SIS1 in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing whether PF3D7_0213100 functions as a bona fide Hsp70 cochaperone required demonstrating both its cellular compartment and a direct effect on Hsp70 activity, which this work provided by placing SIS1 in the cytosol and showing it stimulates PfHsp70-1 ATPase turnover.\",\n      \"evidence\": \"Subcellular fractionation/localization plus in vitro ATPase stimulation and dimerization assays on recombinant SIS1\",\n      \"pmids\": [\"25701168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No physiological client/substrate proteins identified\",\n        \"No structural characterization of the J-domain/PfHsp70-1 interaction\",\n        \"No in vivo essentiality or loss-of-function phenotype established\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether SIS1 shares substrates with the paralogous cochaperone PfYdj1 was resolved by testing ribonucleotide reductase subunit PfR2, showing that PfR2 binds PfHsp70-1 via the Type I cochaperone PfYdj1 but not via the Type II cochaperone SIS1, establishing cochaperone substrate selectivity.\",\n      \"evidence\": \"Co-immunoprecipitation/interaction assays contrasting PfR2 binding to PfYdj1 versus SIS1 in P. falciparum 3D7\",\n      \"pmids\": [\"40938117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative result establishes what SIS1 does not bind, but no positive SIS1-specific client was identified\",\n        \"Molecular basis for the differential selectivity between Type I and Type II cochaperones not defined\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological client repertoire of SIS1 and its role in parasite biology remain undefined.\",\n      \"evidence\": \"No discovery in the corpus identifies a SIS1-specific substrate or an in vivo function\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No positive SIS1 client protein identified\",\n        \"No genetic loss-of-function or essentiality data\",\n        \"No structural model of SIS1 or its Hsp70 engagement\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001671\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0030544\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0042803\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006457\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfHsp70-1 (stimulates its ATPase activity) [#0]\",\n      \"PfR2 ribonucleotide reductase small subunit — does NOT associate with SIS1 [#1]\"\n    ],\n    \"other_free_text\": [\n      \"SIS1 is a Type II J-domain protein (Hsp40 cochaperone), functionally distinguished from the Type I cochaperone PfYdj1 (PF3D7_1437900) by substrate selectivity [#1].\",\n      \"SIS1 forms dimers in vitro [#0].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0213100","name":null,"product":"protein SIS1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0310000","name":null,"product":"protein SIS1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0407900","name":null,"product":"protein SIS1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SIS1","evaluation":null}