Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium.
The ubiquitin-proteasome system (UPS) is essential for Plasmodium falciparum survival and represents a potential target for antimalarial therapies. We utilised a ubiquitin- activity based probe (Ub-Dha) to capture active components of the ubiquitin conjugating machinery during asexual blood-stage de...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-04-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1013032 |
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| author | Cameron Smith Mohsen Hajisadeghian Gerbrand J van der Heden van Noort Michael J Deery Adán Pinto-Fernández Benedikt M Kessler Katerina Artavanis-Tsakonas |
| author_facet | Cameron Smith Mohsen Hajisadeghian Gerbrand J van der Heden van Noort Michael J Deery Adán Pinto-Fernández Benedikt M Kessler Katerina Artavanis-Tsakonas |
| author_sort | Cameron Smith |
| collection | DOAJ |
| description | The ubiquitin-proteasome system (UPS) is essential for Plasmodium falciparum survival and represents a potential target for antimalarial therapies. We utilised a ubiquitin- activity based probe (Ub-Dha) to capture active components of the ubiquitin conjugating machinery during asexual blood-stage development. Several E2 ubiquitin-conjugating enzymes, the E1 activating enzyme, and the HECT E3 ligase PfHEUL were identified and validated through in vitro ubiquitination assays. We also demonstrate selective functional interactions between PfHEUL and a subset of both human and P. falciparum E2s. Additionally, the Ub-Dha probe captured an uncharacterized protein, PF3D7_0811400 (C0H4U0) with no known homology to ubiquitin-pathway enzymes in other organisms. Through structural and biochemical analysis, we validate it as a novel E2 enzyme, capable of binding ubiquitin in a cysteine-specific manner. These findings contribute to our understanding of the P. falciparum UPS, identifying promising novel drug targets and highlighting the evolutionary uniqueness of the Ub-proteasome system in this parasite. |
| format | Article |
| id | doaj-art-0fe378bdbdee49e1a15d1f59227ffa5f |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-0fe378bdbdee49e1a15d1f59227ffa5f2025-08-20T03:14:20ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-04-01214e101303210.1371/journal.ppat.1013032Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium.Cameron SmithMohsen HajisadeghianGerbrand J van der Heden van NoortMichael J DeeryAdán Pinto-FernándezBenedikt M KesslerKaterina Artavanis-TsakonasThe ubiquitin-proteasome system (UPS) is essential for Plasmodium falciparum survival and represents a potential target for antimalarial therapies. We utilised a ubiquitin- activity based probe (Ub-Dha) to capture active components of the ubiquitin conjugating machinery during asexual blood-stage development. Several E2 ubiquitin-conjugating enzymes, the E1 activating enzyme, and the HECT E3 ligase PfHEUL were identified and validated through in vitro ubiquitination assays. We also demonstrate selective functional interactions between PfHEUL and a subset of both human and P. falciparum E2s. Additionally, the Ub-Dha probe captured an uncharacterized protein, PF3D7_0811400 (C0H4U0) with no known homology to ubiquitin-pathway enzymes in other organisms. Through structural and biochemical analysis, we validate it as a novel E2 enzyme, capable of binding ubiquitin in a cysteine-specific manner. These findings contribute to our understanding of the P. falciparum UPS, identifying promising novel drug targets and highlighting the evolutionary uniqueness of the Ub-proteasome system in this parasite.https://doi.org/10.1371/journal.ppat.1013032 |
| spellingShingle | Cameron Smith Mohsen Hajisadeghian Gerbrand J van der Heden van Noort Michael J Deery Adán Pinto-Fernández Benedikt M Kessler Katerina Artavanis-Tsakonas Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium. PLoS Pathogens |
| title | Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium. |
| title_full | Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium. |
| title_fullStr | Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium. |
| title_full_unstemmed | Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium. |
| title_short | Activity-based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in Plasmodium. |
| title_sort | activity based protein profiling reveals both canonical and novel ubiquitin pathway enzymes in plasmodium |
| url | https://doi.org/10.1371/journal.ppat.1013032 |
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