{"gene":"PF3D7_1113400","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2020,"finding":"Crystal structure of the unbound PfDSK2 UBL domain at 1.30 Å resolution revealed an additional 3(10)-helix compared to the human homolog, significant differences in its putative binding interface with proteasomal receptors PfRpn10 and PfRpn13, and a reversal of surface charge on the non-binding face compared to HsDsk2, instead resembling a HOIL-like E3 ligase UBL domain.","method":"X-ray crystallography (crystal structure at 1.30 Å)","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional interface analysis, single lab but atomic-resolution structural data with direct comparison to human homolog","pmids":["32057831"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"PfDSK2 UBL domain binds to proteasomal receptors PfRpn10 and PfRpn13 with dissociation constants of the same order of magnitude as the human system, establishing DSK2 as a proteasome substrate shuttle protein in P. falciparum.","method":"Binding affinity measurement (dissociation constant determination, biophysical assay)","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding affinity measurement with two proteasomal receptors, single lab, quantitative dissociation constants reported","pmids":["32057831"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"A novel interaction was detected between PfRpn13 DEUBAD domain and the PfDSK2 UBL domain, suggesting DSK2 may cooperate with deubiquitinating enzymes for proofreading ubiquitinated substrates.","method":"Binding/interaction assay (biophysical measurement of PfRpn13DEUBAD–PfDSK2UBL interaction)","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single interaction assay reported in one study, novel finding not yet replicated; functional consequence is proposed but not fully experimentally confirmed","pmids":["32057831"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"In a cellular thermal shift assay (CETSA) performed in intact infected red blood cells, DSK2 (PF3D7_1113400) was thermally stabilized by the broad-spectrum cysteine protease inhibitor E64d, indicating direct or indirect physical engagement of DSK2 with E64d in the cellular context; notably, this stabilization was not observed in cell lysate.","method":"Cellular thermal shift assay (CETSA/ITDR) in intact infected erythrocytes","journal":"Medicinal research reviews","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single chemo-proteomics experiment, indirect thermal stabilization readout, no follow-up mechanistic validation, reported in a review paper","pmids":["37232495"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfDSK2 (PF3D7_1113400) is a ubiquitin shuttle protein in P. falciparum whose UBL domain adopts a unique crystal structure (1.30 Å) with an additional 3(10)-helix and distinct surface charge compared to its human homolog; it binds proteasomal receptors PfRpn10 and PfRpn13 with affinities similar to the human system, and also engages the DEUBAD domain of PfRpn13, suggesting a broader interaction landscape that may include cooperation with deubiquitinating enzymes for proofreading ubiquitinated substrates."},"narrative":{"mechanistic_narrative":"DSK2 (PF3D7_1113400) is a ubiquitin-domain-containing shuttle protein of the Plasmodium falciparum ubiquitin-proteasome system that delivers ubiquitinated substrates to the proteasome [PMID:32057831]. Its ubiquitin-like (UBL) domain adopts a distinct fold, resolved crystallographically at 1.30 Å, that carries an additional 3(10)-helix, an altered receptor-binding interface, and a reversed surface charge on its non-binding face relative to the human homolog, more closely resembling a HOIL-like E3 ligase UBL domain [PMID:32057831]. The UBL domain binds the proteasomal receptors PfRpn10 and PfRpn13 with dissociation constants comparable to the human system, consistent with a conserved substrate-delivery role [PMID:32057831], and additionally engages the DEUBAD domain of PfRpn13, indicating an interaction landscape that may extend to cooperation with deubiquitinating enzymes during substrate proofreading [PMID:32057831]. Beyond these structural and binding characterizations, the cellular and phenotypic roles of DSK2 have not been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Whether the P. falciparum DSK2 UBL domain is structurally divergent from its human counterpart was unknown; an atomic-resolution structure established that the parasite domain has a unique architecture and surface chemistry that distinguishes it from HsDsk2.","evidence":"X-ray crystallography of the unbound PfDSK2 UBL domain at 1.30 Å","pmids":["32057831"],"confidence":"High","gaps":["No structure of the full-length protein or of DSK2 in complex with its receptors","Functional consequence of the divergent surface charge and 3(10)-helix is not tested","The C-terminal UBA domain and substrate-binding end are not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"It was unclear whether DSK2 functions as a proteasome shuttle in P. falciparum; quantitative binding to PfRpn10 and PfRpn13 with human-comparable affinities established DSK2 as a substrate shuttle protein.","evidence":"Biophysical dissociation-constant measurement of PfDSK2 UBL binding to PfRpn10 and PfRpn13","pmids":["32057831"],"confidence":"Medium","gaps":["Binding shown for isolated UBL domain, not full-length protein","No demonstration of actual substrate delivery to the proteasome","Cellular requirement of these interactions untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Whether DSK2 could couple to deubiquitinating machinery was unknown; detection of a UBL–DEUBAD interaction with PfRpn13 hinted at a broader role in substrate proofreading.","evidence":"Biophysical interaction assay between PfRpn13 DEUBAD domain and PfDSK2 UBL domain","pmids":["32057831"],"confidence":"Medium","gaps":["Single interaction assay, not independently replicated","Functional consequence for deubiquitination or proofreading is proposed but not tested","No evidence of a ternary DSK2–Rpn13–DUB assembly"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Whether DSK2 is engaged in the cellular context by protease inhibitors was unexplored; thermal stabilization by E64d in intact infected erythrocytes indicated direct or indirect physical engagement of DSK2 in cells.","evidence":"Cellular thermal shift assay (CETSA/ITDR) with E64d in intact infected red blood cells; stabilization absent in lysate","pmids":["37232495"],"confidence":"Low","gaps":["Single chemo-proteomics experiment with an indirect thermal-stabilization readout and no mechanistic follow-up","Cannot distinguish direct binding from indirect engagement, especially given the lysate-negative result","No demonstration that E64d targets DSK2 function"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The cellular function, essentiality, substrate repertoire, and in vivo role of DSK2 in the P. falciparum proteasome pathway remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genetic knockout or knockdown phenotype reported","No ubiquitinated substrates identified","No demonstration of proteasomal delivery in vivo"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFRPN10 (PROTEASOMAL RECEPTOR)","PFRPN13 (PROTEASOMAL RECEPTOR, INCLUDING ITS DEUBAD DOMAIN)"],"other_free_text":["UBL domain crystal structure at 1.30 Å shows an additional 3(10)-helix and reversed non-binding-face surface charge relative to HsDsk2, resembling a HOIL-like E3 ligase UBL domain [#0]","Thermally stabilized by the cysteine protease inhibitor E64d in intact infected erythrocytes but not in lysate [#3]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"32057831","id":"PMC_32057831","title":"The recognition of proteasomal receptors by Plasmodium falciparum DSK2.","date":"2020","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/32057831","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DSK2","PfDSK2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40278767","id":"","title":"Combating Malaria: Targeting the Ubiquitin-Proteasome System to Conquer Drug Resistance.","date":"2025","source":"Tropical medicine and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/40278767","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DSK2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39497850","id":"","title":"Ubiquitin-proteasome system in Plasmodium: a potential antimalarial target to overcome resistance - a systematic review.","date":"2024","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39497850","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DSK2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41373862","id":"","title":"Characterization of the Regulatory AAA-ATPase Subunit Rpt3 in Plasmodium berghei as an Activator of Protein Phosphatase 1.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41373862","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DSK2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34780541","id":"","title":"A conserved guided entry of tail-anchored pathway is involved in the trafficking of a subset of membrane proteins in Plasmodium falciparum.","date":"2021","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/34780541","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DSK2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34832620","id":"","title":"Artemisinin Binds and Inhibits the Activity of Plasmodium falciparum Ddi1, a Retroviral Aspartyl Protease.","date":"2021","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34832620","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DSK2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37232495","id":"","title":"Chemo-proteomics in antimalarial target identification and engagement.","date":"2023","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/37232495","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DSK2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18545708","id":"","title":"Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: a potential strategy to interfere with parasite virulence.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18545708","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DSK2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11665,"output_tokens":1165,"usd":0.026235,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6020,"output_tokens":2215,"usd":0.042737,"stage2_stop_reason":"end_turn"},"total_usd":0.068972,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the unbound PfDSK2 UBL domain at 1.30 Å resolution revealed an additional 3(10)-helix compared to the human homolog, significant differences in its putative binding interface with proteasomal receptors PfRpn10 and PfRpn13, and a reversal of surface charge on the non-binding face compared to HsDsk2, instead resembling a HOIL-like E3 ligase UBL domain.\",\n      \"method\": \"X-ray crystallography (crystal structure at 1.30 Å)\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional interface analysis, single lab but atomic-resolution structural data with direct comparison to human homolog\",\n      \"pmids\": [\"32057831\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PfDSK2 UBL domain binds to proteasomal receptors PfRpn10 and PfRpn13 with dissociation constants of the same order of magnitude as the human system, establishing DSK2 as a proteasome substrate shuttle protein in P. falciparum.\",\n      \"method\": \"Binding affinity measurement (dissociation constant determination, biophysical assay)\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding affinity measurement with two proteasomal receptors, single lab, quantitative dissociation constants reported\",\n      \"pmids\": [\"32057831\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A novel interaction was detected between PfRpn13 DEUBAD domain and the PfDSK2 UBL domain, suggesting DSK2 may cooperate with deubiquitinating enzymes for proofreading ubiquitinated substrates.\",\n      \"method\": \"Binding/interaction assay (biophysical measurement of PfRpn13DEUBAD–PfDSK2UBL interaction)\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single interaction assay reported in one study, novel finding not yet replicated; functional consequence is proposed but not fully experimentally confirmed\",\n      \"pmids\": [\"32057831\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In a cellular thermal shift assay (CETSA) performed in intact infected red blood cells, DSK2 (PF3D7_1113400) was thermally stabilized by the broad-spectrum cysteine protease inhibitor E64d, indicating direct or indirect physical engagement of DSK2 with E64d in the cellular context; notably, this stabilization was not observed in cell lysate.\",\n      \"method\": \"Cellular thermal shift assay (CETSA/ITDR) in intact infected erythrocytes\",\n      \"journal\": \"Medicinal research reviews\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single chemo-proteomics experiment, indirect thermal stabilization readout, no follow-up mechanistic validation, reported in a review paper\",\n      \"pmids\": [\"37232495\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfDSK2 (PF3D7_1113400) is a ubiquitin shuttle protein in P. falciparum whose UBL domain adopts a unique crystal structure (1.30 Å) with an additional 3(10)-helix and distinct surface charge compared to its human homolog; it binds proteasomal receptors PfRpn10 and PfRpn13 with affinities similar to the human system, and also engages the DEUBAD domain of PfRpn13, suggesting a broader interaction landscape that may include cooperation with deubiquitinating enzymes for proofreading ubiquitinated substrates.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DSK2 (PF3D7_1113400) is a ubiquitin-domain-containing shuttle protein of the Plasmodium falciparum ubiquitin-proteasome system that delivers ubiquitinated substrates to the proteasome [#1]. Its ubiquitin-like (UBL) domain adopts a distinct fold, resolved crystallographically at 1.30 Å, that carries an additional 3(10)-helix, an altered receptor-binding interface, and a reversed surface charge on its non-binding face relative to the human homolog, more closely resembling a HOIL-like E3 ligase UBL domain [#0]. The UBL domain binds the proteasomal receptors PfRpn10 and PfRpn13 with dissociation constants comparable to the human system, consistent with a conserved substrate-delivery role [#1], and additionally engages the DEUBAD domain of PfRpn13, indicating an interaction landscape that may extend to cooperation with deubiquitinating enzymes during substrate proofreading [#2]. Beyond these structural and binding characterizations, the cellular and phenotypic roles of DSK2 have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether the P. falciparum DSK2 UBL domain is structurally divergent from its human counterpart was unknown; an atomic-resolution structure established that the parasite domain has a unique architecture and surface chemistry that distinguishes it from HsDsk2.\",\n      \"evidence\": \"X-ray crystallography of the unbound PfDSK2 UBL domain at 1.30 Å\",\n      \"pmids\": [\"32057831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the full-length protein or of DSK2 in complex with its receptors\",\n        \"Functional consequence of the divergent surface charge and 3(10)-helix is not tested\",\n        \"The C-terminal UBA domain and substrate-binding end are not resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"It was unclear whether DSK2 functions as a proteasome shuttle in P. falciparum; quantitative binding to PfRpn10 and PfRpn13 with human-comparable affinities established DSK2 as a substrate shuttle protein.\",\n      \"evidence\": \"Biophysical dissociation-constant measurement of PfDSK2 UBL binding to PfRpn10 and PfRpn13\",\n      \"pmids\": [\"32057831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding shown for isolated UBL domain, not full-length protein\",\n        \"No demonstration of actual substrate delivery to the proteasome\",\n        \"Cellular requirement of these interactions untested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether DSK2 could couple to deubiquitinating machinery was unknown; detection of a UBL–DEUBAD interaction with PfRpn13 hinted at a broader role in substrate proofreading.\",\n      \"evidence\": \"Biophysical interaction assay between PfRpn13 DEUBAD domain and PfDSK2 UBL domain\",\n      \"pmids\": [\"32057831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single interaction assay, not independently replicated\",\n        \"Functional consequence for deubiquitination or proofreading is proposed but not tested\",\n        \"No evidence of a ternary DSK2–Rpn13–DUB assembly\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether DSK2 is engaged in the cellular context by protease inhibitors was unexplored; thermal stabilization by E64d in intact infected erythrocytes indicated direct or indirect physical engagement of DSK2 in cells.\",\n      \"evidence\": \"Cellular thermal shift assay (CETSA/ITDR) with E64d in intact infected red blood cells; stabilization absent in lysate\",\n      \"pmids\": [\"37232495\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single chemo-proteomics experiment with an indirect thermal-stabilization readout and no mechanistic follow-up\",\n        \"Cannot distinguish direct binding from indirect engagement, especially given the lysate-negative result\",\n        \"No demonstration that E64d targets DSK2 function\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cellular function, essentiality, substrate repertoire, and in vivo role of DSK2 in the P. falciparum proteasome pathway remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genetic knockout or knockdown phenotype reported\",\n        \"No ubiquitinated substrates identified\",\n        \"No demonstration of proteasomal delivery in vivo\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031593\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140036\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0043161\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfRpn10 (proteasomal receptor)\",\n      \"PfRpn13 (proteasomal receptor, including its DEUBAD domain)\"\n    ],\n    \"other_free_text\": [\n      \"UBL domain crystal structure at 1.30 Å shows an additional 3(10)-helix and reversed non-binding-face surface charge relative to HsDsk2, resembling a HOIL-like E3 ligase UBL domain [#0]\",\n      \"Thermally stabilized by the cysteine protease inhibitor E64d in intact infected erythrocytes but not in lysate [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1113400","name":null,"product":"ubiquitin domain-containing protein DSK2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0934200","name":null,"product":"ubiquitin domain-containing protein DSK2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0911000","name":null,"product":"ubiquitin domain-containing protein DSK2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"DSK2","evaluation":null}