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bioRxiv · 10.1101/2024.10.06.616869

Identification of a new Plasmodium falciparum E2 ubiquitin conjugating enzyme

Smith, C.·Hajisadeghian, M.·van der Heden van Noort, G. J.·Pinto-Fernandez, A.·Kessler, B. M.·Artavanis-Tsakonas, K.
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Abstract

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.

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Smith, C., Hajisadeghian, M., van der Heden van Noort, G. J., Pinto-Fernandez, A., Kessler, B. M., Artavanis-Tsakonas, K.. 2024-10-06. Identification of a new Plasmodium falciparum E2 ubiquitin conjugating enzyme. https://doi.org/10.1101/2024.10.06.616869

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