Identification of a new Plasmodium falciparum E2 ubiquitin conjugating enzyme

Internet publication

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.

Authors: Smith, C; Hajisadeghian, M; van der Heden van Noort, GJ; Pinto-Fernandez, A; Kessler, BM

• Publication status: Published
• Peer review status: Not peer reviewed
• Host title: bioarXiv
• Publication date: 2024-10-06
• DOI: 10.1101/2024.10.06.616869
• Language: English