{"gene":"PF3D7_1356300","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2015,"finding":"X-ray crystallography of the human SUMO E1 ubiquitin fold domain in complex with E2 (Ubc9), combined with in silico modeling, mutagenesis, and in vitro biochemical studies of the P. falciparum SUMO E1 and E2 enzymes, identified surface residues that explain species-specific E1-E2 interactions in the P. falciparum SUMOylation system. The P. falciparum E1-E2 interface is distinct from the human interface, suggesting a parasite-specific interaction mechanism.","method":"X-ray crystallography, in silico modeling, site-directed mutagenesis, in vitro biochemical assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — 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 (requiring E2/Ubc9) plays a role in the P. falciparum parasite response to oxidative stress during red blood cell (trophozoite) stages, indicative of a protective role, as demonstrated by susceptibility of trophozoites to iron-induced oxidative stress when SUMOylation is perturbed.","method":"In vitro parasite culture with oxidative stress challenge; biochemical analysis of SUMOylation pathway activity","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single method (stress assay), no direct KO of E2 reported in abstract","pmids":["26697886"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"Biochemical and biophysical analyses demonstrated a unidirectional cross-species interaction: Pf-SUMO interacts with human E2 (Hs-Ubc9), but human SUMO1 (Hs-SUMO1) fails to interact with Pf-E2 (PF3D7_1356300/Ubc9). Surface-accessible aspartates of Pf-SUMO determine the efficacy and specificity of SUMO-E2 interactions, and critical residues of the Pf-E2 N-terminus are responsible for the diminished Hs-SUMO1/Pf-E2 interaction. Mutating these Pf-E2 residues to corresponding human residues restores cross-species interaction.","method":"Biochemical interaction assays (binding/conjugation), biophysical analyses, site-directed mutagenesis","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal biochemical/biophysical methods with mutagenesis, but single lab and limited replication","pmids":["35331687"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1356300 encodes the SUMO E2-conjugating enzyme (Ubc9) in P. falciparum, whose E1-binding interface is structurally and functionally distinct from the human counterpart due to specific surface residues at its N-terminus, conferring species-specific E1-E2 interactions within the parasite SUMOylation pathway, which itself plays a protective role during oxidative stress in intraerythrocytic stages."},"narrative":{"mechanistic_narrative":"PF3D7_1356300 encodes the SUMO E2-conjugating enzyme (Ubc9) of Plasmodium falciparum, functioning within the parasite SUMOylation pathway [PMID:26697886]. X-ray crystallography of the human SUMO E1–E2 complex combined with in silico modeling, mutagenesis, and in vitro biochemistry of the P. falciparum SUMO E1 and E2 enzymes established that the P. falciparum E1–E2 interface is distinct from its human counterpart, defining a parasite-specific E1–E2 interaction mechanism [PMID:26697886]. Interaction specificity extends to the SUMO substrate: Pf-SUMO can engage human Ubc9, but human SUMO1 fails to interact with Pf-E2, and critical N-terminal residues of Pf-E2 are responsible for this diminished cross-species interaction, since mutating them to the corresponding human residues restores binding [PMID:35331687]. Perturbation of SUMOylation, which requires E2/Ubc9, sensitizes trophozoite-stage parasites to iron-induced oxidative stress, indicating a protective role for the pathway during intraerythrocytic development [PMID:26697886]. Beyond these species-specificity determinants and the oxidative-stress phenotype, the substrate repertoire and broader regulatory functions of PF3D7_1356300 have not been characterized in the available corpus.","teleology":[{"year":2015,"claim":"It was unknown whether the parasite SUMO conjugation machinery could be targeted selectively; determining the E1–E2 interface established that PF3D7_1356300 engages its E1 through a parasite-specific surface distinct from the human enzyme.","evidence":"X-ray crystallography of the human SUMO E1–E2 complex with in silico modeling, site-directed mutagenesis, and in vitro biochemical assays of P. falciparum E1 and E2","pmids":["26697886"],"confidence":"High","gaps":["No crystal structure of the P. falciparum E1–E2 complex itself was solved","Physiological consequences of disrupting the parasite-specific interface in vivo not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"The cellular purpose of SUMOylation in the parasite was unclear; linking pathway activity to oxidative-stress tolerance established a protective role during the trophozoite stage.","evidence":"In vitro parasite culture with iron-induced oxidative stress challenge and biochemical analysis of SUMOylation activity","pmids":["26697886"],"confidence":"Medium","gaps":["No direct knockout of PF3D7_1356300 reported","Substrates SUMOylated during oxidative stress not identified","Single lab, single stress assay"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Whether SUMO–E2 recognition is species-specific was open; cross-species binding assays established that the Pf-E2 N-terminus dictates a unidirectional interaction with SUMO and can be humanized to restore binding.","evidence":"Biochemical interaction/conjugation assays, biophysical analyses, and site-directed mutagenesis of Pf-SUMO and Pf-E2 residues","pmids":["35331687"],"confidence":"Medium","gaps":["Structural basis of the N-terminal specificity residues not resolved","Downstream substrate consequences of altered SUMO–E2 specificity untested","Single lab, limited replication"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The substrate repertoire, in vivo essentiality, and full E3/target network of PF3D7_1356300 across the parasite life cycle remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No SUMO-conjugation substrates of PF3D7_1356300 identified","No genetic loss-of-function characterization","Role outside the trophozoite/oxidative-stress context unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["SUMO E1 ACTIVATING ENZYME (P. FALCIPARUM)","PF-SUMO"],"other_free_text":["PF3D7_1356300 is the P. falciparum SUMO E2-conjugating enzyme (Ubc9); its E1-binding interface differs from the human enzyme [#0].","N-terminal residues of Pf-E2 confer species-specific SUMO recognition and can be humanized to restore cross-species interaction [#2].","SUMOylation requiring this E2 protects trophozoite-stage parasites against iron-induced oxidative stress [#1]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"28577368","id":"PMC_28577368","title":"Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads.","date":"2017","source":"BMC pharmacology & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/28577368","citation_count":23,"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":"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":4477,"output_tokens":1022,"usd":0.01438,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5761,"output_tokens":1970,"usd":0.039027,"stage2_stop_reason":"end_turn"},"total_usd":0.053407,"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\": 2015,\n      \"finding\": \"X-ray crystallography of the human SUMO E1 ubiquitin fold domain in complex with E2 (Ubc9), combined with in silico modeling, mutagenesis, and in vitro biochemical studies of the P. falciparum SUMO E1 and E2 enzymes, identified surface residues that explain species-specific E1-E2 interactions in the P. falciparum SUMOylation system. The P. falciparum E1-E2 interface is distinct from the human interface, suggesting a parasite-specific interaction mechanism.\",\n      \"method\": \"X-ray crystallography, in silico modeling, site-directed mutagenesis, in vitro biochemical assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — 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 (requiring E2/Ubc9) plays a role in the P. falciparum parasite response to oxidative stress during red blood cell (trophozoite) stages, indicative of a protective role, as demonstrated by susceptibility of trophozoites to iron-induced oxidative stress when SUMOylation is perturbed.\",\n      \"method\": \"In vitro parasite culture with oxidative stress challenge; biochemical analysis of SUMOylation pathway activity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (stress assay), no direct KO of E2 reported in abstract\",\n      \"pmids\": [\"26697886\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biochemical and biophysical analyses demonstrated a unidirectional cross-species interaction: Pf-SUMO interacts with human E2 (Hs-Ubc9), but human SUMO1 (Hs-SUMO1) fails to interact with Pf-E2 (PF3D7_1356300/Ubc9). Surface-accessible aspartates of Pf-SUMO determine the efficacy and specificity of SUMO-E2 interactions, and critical residues of the Pf-E2 N-terminus are responsible for the diminished Hs-SUMO1/Pf-E2 interaction. Mutating these Pf-E2 residues to corresponding human residues restores cross-species interaction.\",\n      \"method\": \"Biochemical interaction assays (binding/conjugation), biophysical analyses, site-directed mutagenesis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal biochemical/biophysical methods with mutagenesis, but single lab and limited replication\",\n      \"pmids\": [\"35331687\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1356300 encodes the SUMO E2-conjugating enzyme (Ubc9) in P. falciparum, whose E1-binding interface is structurally and functionally distinct from the human counterpart due to specific surface residues at its N-terminus, conferring species-specific E1-E2 interactions within the parasite SUMOylation pathway, which itself plays a protective role during oxidative stress in intraerythrocytic stages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1356300 encodes the SUMO E2-conjugating enzyme (Ubc9) of Plasmodium falciparum, functioning within the parasite SUMOylation pathway [#0]. X-ray crystallography of the human SUMO E1–E2 complex combined with in silico modeling, mutagenesis, and in vitro biochemistry of the P. falciparum SUMO E1 and E2 enzymes established that the P. falciparum E1–E2 interface is distinct from its human counterpart, defining a parasite-specific E1–E2 interaction mechanism [#0]. Interaction specificity extends to the SUMO substrate: Pf-SUMO can engage human Ubc9, but human SUMO1 fails to interact with Pf-E2, and critical N-terminal residues of Pf-E2 are responsible for this diminished cross-species interaction, since mutating them to the corresponding human residues restores binding [#2]. Perturbation of SUMOylation, which requires E2/Ubc9, sensitizes trophozoite-stage parasites to iron-induced oxidative stress, indicating a protective role for the pathway during intraerythrocytic development [#1]. Beyond these species-specificity determinants and the oxidative-stress phenotype, the substrate repertoire and broader regulatory functions of PF3D7_1356300 have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"It was unknown whether the parasite SUMO conjugation machinery could be targeted selectively; determining the E1–E2 interface established that PF3D7_1356300 engages its E1 through a parasite-specific surface distinct from the human enzyme.\",\n      \"evidence\": \"X-ray crystallography of the human SUMO E1–E2 complex with in silico modeling, site-directed mutagenesis, and in vitro biochemical assays of P. falciparum E1 and E2\",\n      \"pmids\": [\"26697886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the P. falciparum E1–E2 complex itself was solved\", \"Physiological consequences of disrupting the parasite-specific interface in vivo not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The cellular purpose of SUMOylation in the parasite was unclear; linking pathway activity to oxidative-stress tolerance established a protective role during the trophozoite stage.\",\n      \"evidence\": \"In vitro parasite culture with iron-induced oxidative stress challenge and biochemical analysis of SUMOylation activity\",\n      \"pmids\": [\"26697886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct knockout of PF3D7_1356300 reported\", \"Substrates SUMOylated during oxidative stress not identified\", \"Single lab, single stress assay\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether SUMO–E2 recognition is species-specific was open; cross-species binding assays established that the Pf-E2 N-terminus dictates a unidirectional interaction with SUMO and can be humanized to restore binding.\",\n      \"evidence\": \"Biochemical interaction/conjugation assays, biophysical analyses, and site-directed mutagenesis of Pf-SUMO and Pf-E2 residues\",\n      \"pmids\": [\"35331687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the N-terminal specificity residues not resolved\", \"Downstream substrate consequences of altered SUMO–E2 specificity untested\", \"Single lab, limited replication\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The substrate repertoire, in vivo essentiality, and full E3/target network of PF3D7_1356300 across the parasite life cycle remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No SUMO-conjugation substrates of PF3D7_1356300 identified\", \"No genetic loss-of-function characterization\", \"Role outside the trophozoite/oxidative-stress context unknown\"],\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:0016929\", \"supporting_discovery_ids\": [0, 1, 2]}\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\": [\"SUMO E1 activating enzyme (P. falciparum)\", \"Pf-SUMO\"],\n    \"other_free_text\": [\n      \"PF3D7_1356300 is the P. falciparum SUMO E2-conjugating enzyme (Ubc9); its E1-binding interface differs from the human enzyme [#0].\",\n      \"N-terminal residues of Pf-E2 confer species-specific SUMO recognition and can be humanized to restore cross-species interaction [#2].\",\n      \"SUMOylation requiring this E2 protects trophozoite-stage parasites against iron-induced oxidative stress [#1].\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1356300","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_1356300","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1132600","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1115200","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}