{"gene":"PF3D7_0921000","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2015,"finding":"The P. falciparum SUMO E2-conjugating enzyme (PF3D7_0921000/Pf-E2) interacts with the P. falciparum SUMO E1-activating enzyme through species-specific surface residues that are distinct from those mediating the human E1–E2 (Ubc9) interaction; mutagenesis and in vitro biochemical studies identified specific surface residues on both the Pf E1 UFD domain and Pf E2 that explain this species-specific selectivity.","method":"X-ray crystallography of human SUMO E1 UFD–Ubc9 complex, in silico modeling of Pf counterparts, site-directed mutagenesis, and in vitro biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus in vitro biochemical validation in a single rigorous study","pmids":["26697886"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"SUMOylation (in which PF3D7_0921000/Pf-E2 participates as the E2-conjugating enzyme) plays a protective role in P. falciparum during iron-induced oxidative stress in red blood cell asexual trophozoite stages, as evidenced by perturbation of the SUMOylation pathway affecting parasite survival under oxidative conditions.","method":"Cell-based experiments exposing P. falciparum asexual trophozoites to iron-induced oxidative stress with assessment of SUMOylation pathway activity","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, indirect cellular assay; pathway role attributed to the SUMOylation system broadly with E2 as a component","pmids":["26697886"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"A unidirectional cross-species interaction exists in which Pf-SUMO can interact with human E2 (Hs-Ubc9), but Hs-SUMO1 fails to interact with Pf-E2 (PF3D7_0921000); critical residues at the N-terminus of Pf-E2 are responsible for this diminished interaction with Hs-SUMO1, and mutating these residues to corresponding Hs-Ubc9 residues restores electrostatic, π-π, and hydrophobic interactions enabling efficient cross-species binding.","method":"Biochemical and biophysical analyses (binding assays), site-directed mutagenesis of Pf-E2 N-terminal residues, electrostatic and interaction modeling","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with multiple biophysical methods in a single lab study","pmids":["35331687"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0921000 (Pf-E2/Pf-Ubc9) is the SUMO E2-conjugating enzyme in P. falciparum whose interaction with the Pf SUMO E1-activating enzyme is governed by species-specific surface residues—particularly at its N-terminus—that distinguish it from the human system, confer unidirectional cross-species SUMO selectivity, and enable its protective role in the parasite's response to oxidative stress during asexual blood stages."},"narrative":{"mechanistic_narrative":"PF3D7_0921000 (Pf-E2) is the SUMO E2-conjugating enzyme of Plasmodium falciparum, functioning within the parasite's SUMOylation pathway [PMID:26697886]. It engages the P. falciparum SUMO E1-activating enzyme through species-specific surface residues distinct from those mediating the human E1–E2 interaction, with defined residues on both the Pf E1 UFD domain and Pf E2 accounting for this selectivity [PMID:26697886]. The N-terminus of Pf-E2 further governs SUMO recognition: it drives a unidirectional cross-species selectivity in which Pf-SUMO can interact with human E2 while human SUMO1 fails to engage Pf-E2, and mutating N-terminal Pf-E2 residues to their human counterparts restores electrostatic, π-π, and hydrophobic contacts sufficient for cross-species binding [PMID:35331687]. Functionally, the SUMOylation pathway in which Pf-E2 acts as the E2 component plays a protective role during iron-induced oxidative stress in asexual trophozoite-stage parasites [PMID:26697886]. Beyond its role in E1 engagement, SUMO recognition, and oxidative-stress protection, the substrate repertoire and downstream targets of Pf-E2 have not been characterized in the available corpus.","teleology":[{"year":2015,"claim":"It was unknown how the parasite SUMO E2 enzyme is distinguished from its human counterpart; this study established that Pf-E2 engages the Pf SUMO E1-activating enzyme via species-specific surface residues, defining a divergent E1–E2 interface exploitable for selective targeting.","evidence":"X-ray crystallography of the human SUMO E1 UFD–Ubc9 complex, in silico modeling of Pf counterparts, site-directed mutagenesis, and in vitro binding assays","pmids":["26697886"],"confidence":"High","gaps":["No structure of the actual Pf E1–Pf E2 complex was solved; the Pf interface rests on modeling and mutagenesis","SUMO substrates conjugated by Pf-E2 were not identified","Catalytic thioester-transfer activity of Pf-E2 was not directly demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"The physiological importance of parasite SUMOylation was unclear; perturbation experiments showed the pathway, with Pf-E2 as its E2 component, protects asexual trophozoites against iron-induced oxidative stress, linking the conjugation machinery to a stress-response function.","evidence":"Cell-based exposure of P. falciparum asexual trophozoites to iron-induced oxidative stress with assessment of SUMOylation pathway activity","pmids":["26697886"],"confidence":"Medium","gaps":["The role is attributed to the SUMOylation pathway broadly rather than to Pf-E2 specifically","No direct genetic knockout or knockdown of PF3D7_0921000 was reported","The SUMO-modified targets mediating oxidative-stress protection are unidentified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"It was unknown why Pf and human SUMO systems are not freely interchangeable; this work showed a unidirectional cross-species interaction and mapped the block to N-terminal Pf-E2 residues, defining the structural determinants of SUMO–E2 recognition specificity.","evidence":"Biochemical/biophysical binding assays, site-directed mutagenesis of Pf-E2 N-terminal residues, and electrostatic/interaction modeling","pmids":["35331687"],"confidence":"Medium","gaps":["Mutagenesis-and-modeling study from a single lab without an experimental co-complex structure","Functional consequence of restored cross-species binding for downstream conjugation was not tested","Whether N-terminal residues also affect Pf-E2 interaction with the native Pf-SUMO was not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The substrate repertoire, in-cell essentiality, and catalytic dynamics of Pf-E2 remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No SUMO substrates conjugated by Pf-E2 have been identified","No genetic essentiality data for PF3D7_0921000 in the corpus","No experimental structure of the Pf E1–E2 or Pf E2–SUMO complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["P. FALCIPARUM SUMO E1-ACTIVATING ENZYME (UFD DOMAIN)","PF-SUMO","HUMAN SUMO1 (FAILS TO BIND PF-E2)"],"other_free_text":["Species-specific E1–E2 interface residues distinguish Pf-E2 from human Ubc9 [#0]","N-terminal residues of Pf-E2 govern unidirectional cross-species SUMO selectivity [#2]","SUMOylation pathway containing Pf-E2 protects asexual trophozoites against iron-induced oxidative stress [#1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"26697886","id":"PMC_26697886","title":"Characterization and Structural Insights into Selective E1-E2 Interactions in the Human and Plasmodium falciparum SUMO Conjugation Systems.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26697886","citation_count":14,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ubiquitin-conjugating enzyme E2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35331687","id":"PMC_35331687","title":"Implications of critical node-dependent unidirectional cross-talk of Plasmodium SUMO pathway proteins.","date":"2022","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/35331687","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfE2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3758,"output_tokens":1051,"usd":0.01352,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5805,"output_tokens":2199,"usd":0.042,"stage2_stop_reason":"end_turn"},"total_usd":0.05552,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"The P. falciparum SUMO E2-conjugating enzyme (PF3D7_0921000/Pf-E2) interacts with the P. falciparum SUMO E1-activating enzyme through species-specific surface residues that are distinct from those mediating the human E1–E2 (Ubc9) interaction; mutagenesis and in vitro biochemical studies identified specific surface residues on both the Pf E1 UFD domain and Pf E2 that explain this species-specific selectivity.\",\n      \"method\": \"X-ray crystallography of human SUMO E1 UFD–Ubc9 complex, in silico modeling of Pf counterparts, site-directed mutagenesis, and in vitro biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus in vitro biochemical validation in a single rigorous study\",\n      \"pmids\": [\"26697886\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SUMOylation (in which PF3D7_0921000/Pf-E2 participates as the E2-conjugating enzyme) plays a protective role in P. falciparum during iron-induced oxidative stress in red blood cell asexual trophozoite stages, as evidenced by perturbation of the SUMOylation pathway affecting parasite survival under oxidative conditions.\",\n      \"method\": \"Cell-based experiments exposing P. falciparum asexual trophozoites to iron-induced oxidative stress with assessment of SUMOylation pathway activity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect cellular assay; pathway role attributed to the SUMOylation system broadly with E2 as a component\",\n      \"pmids\": [\"26697886\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A unidirectional cross-species interaction exists in which Pf-SUMO can interact with human E2 (Hs-Ubc9), but Hs-SUMO1 fails to interact with Pf-E2 (PF3D7_0921000); critical residues at the N-terminus of Pf-E2 are responsible for this diminished interaction with Hs-SUMO1, and mutating these residues to corresponding Hs-Ubc9 residues restores electrostatic, π-π, and hydrophobic interactions enabling efficient cross-species binding.\",\n      \"method\": \"Biochemical and biophysical analyses (binding assays), site-directed mutagenesis of Pf-E2 N-terminal residues, electrostatic and interaction modeling\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with multiple biophysical methods in a single lab study\",\n      \"pmids\": [\"35331687\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_0921000 (Pf-E2/Pf-Ubc9) is the SUMO E2-conjugating enzyme in P. falciparum whose interaction with the Pf SUMO E1-activating enzyme is governed by species-specific surface residues—particularly at its N-terminus—that distinguish it from the human system, confer unidirectional cross-species SUMO selectivity, and enable its protective role in the parasite's response to oxidative stress during asexual blood stages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0921000 (Pf-E2) is the SUMO E2-conjugating enzyme of Plasmodium falciparum, functioning within the parasite's SUMOylation pathway [#0]. It engages the P. falciparum SUMO E1-activating enzyme through species-specific surface residues distinct from those mediating the human E1–E2 interaction, with defined residues on both the Pf E1 UFD domain and Pf E2 accounting for this selectivity [#0]. The N-terminus of Pf-E2 further governs SUMO recognition: it drives a unidirectional cross-species selectivity in which Pf-SUMO can interact with human E2 while human SUMO1 fails to engage Pf-E2, and mutating N-terminal Pf-E2 residues to their human counterparts restores electrostatic, π-π, and hydrophobic contacts sufficient for cross-species binding [#2]. Functionally, the SUMOylation pathway in which Pf-E2 acts as the E2 component plays a protective role during iron-induced oxidative stress in asexual trophozoite-stage parasites [#1]. Beyond its role in E1 engagement, SUMO recognition, and oxidative-stress protection, the substrate repertoire and downstream targets of Pf-E2 have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"It was unknown how the parasite SUMO E2 enzyme is distinguished from its human counterpart; this study established that Pf-E2 engages the Pf SUMO E1-activating enzyme via species-specific surface residues, defining a divergent E1–E2 interface exploitable for selective targeting.\",\n      \"evidence\": \"X-ray crystallography of the human SUMO E1 UFD–Ubc9 complex, in silico modeling of Pf counterparts, site-directed mutagenesis, and in vitro binding assays\",\n      \"pmids\": [\"26697886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the actual Pf E1–Pf E2 complex was solved; the Pf interface rests on modeling and mutagenesis\",\n        \"SUMO substrates conjugated by Pf-E2 were not identified\",\n        \"Catalytic thioester-transfer activity of Pf-E2 was not directly demonstrated\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The physiological importance of parasite SUMOylation was unclear; perturbation experiments showed the pathway, with Pf-E2 as its E2 component, protects asexual trophozoites against iron-induced oxidative stress, linking the conjugation machinery to a stress-response function.\",\n      \"evidence\": \"Cell-based exposure of P. falciparum asexual trophozoites to iron-induced oxidative stress with assessment of SUMOylation pathway activity\",\n      \"pmids\": [\"26697886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The role is attributed to the SUMOylation pathway broadly rather than to Pf-E2 specifically\",\n        \"No direct genetic knockout or knockdown of PF3D7_0921000 was reported\",\n        \"The SUMO-modified targets mediating oxidative-stress protection are unidentified\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"It was unknown why Pf and human SUMO systems are not freely interchangeable; this work showed a unidirectional cross-species interaction and mapped the block to N-terminal Pf-E2 residues, defining the structural determinants of SUMO–E2 recognition specificity.\",\n      \"evidence\": \"Biochemical/biophysical binding assays, site-directed mutagenesis of Pf-E2 N-terminal residues, and electrostatic/interaction modeling\",\n      \"pmids\": [\"35331687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mutagenesis-and-modeling study from a single lab without an experimental co-complex structure\",\n        \"Functional consequence of restored cross-species binding for downstream conjugation was not tested\",\n        \"Whether N-terminal residues also affect Pf-E2 interaction with the native Pf-SUMO was not resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The substrate repertoire, in-cell essentiality, and catalytic dynamics of Pf-E2 remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No SUMO substrates conjugated by Pf-E2 have been identified\",\n        \"No genetic essentiality data for PF3D7_0921000 in the corpus\",\n        \"No experimental structure of the Pf E1–E2 or Pf E2–SUMO complex\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0061656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0019789\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016925\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0006979\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"P. falciparum SUMO E1-activating enzyme (UFD domain)\",\n      \"Pf-SUMO\",\n      \"Human SUMO1 (fails to bind Pf-E2)\"\n    ],\n    \"other_free_text\": [\n      \"Species-specific E1–E2 interface residues distinguish Pf-E2 from human Ubc9 [#0]\",\n      \"N-terminal residues of Pf-E2 govern unidirectional cross-species SUMO selectivity [#2]\",\n      \"SUMOylation pathway containing Pf-E2 protects asexual trophozoites against iron-induced oxidative stress [#1]\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_0921000","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 2 of 2 cited papers name other catalogue genes (PF3D7_0505800, PF3D7_0915100). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0921000","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0821900","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0719000","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}