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| Main Authors: | , , , , , , , , , , , |
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| Format: | Artículo Open Access |
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Wiley
2025
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| Online Access: | https://onlinelibrary.wiley.com/doi/10.1002/prot.26813 |
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Table of Contents:
- Understanding the Role of RING ‐Between‐ RING E3 Ligase of the Human Malaria Parasite Varsha Kumari Seema Vidyarthi Aradhya Tripathi Nirupa Chaurasia Niharika Rai Richa Shukla Shagufa Nisrat Noorie Girdhar Bhati Simmi Anjum Mohammad Anas Shakil Ahmed Niti Kumar Proteins: Structure, Function, and Bioinformatics ABSTRACT E3 ligases constitute an important component of proteostasis machinery, which plays a critical role in the survival of malaria parasites through post‐translational modifications of their protein substrates. In contrast to humans, parasite E3 ligases have not been extensively studied. Here, we characterize a unique Plasmodium E3 ligase that has both RING and HECT‐like features with zinc‐coordinating domains. Plasmodium encodes a single RING‐between‐RING (RBR) E3 ligase that has evolutionarily diverged from human and other intracellular parasites. This RBR‐E3 ligase is expressed throughout the erythrocytic phase of the P. falciparum lifecycle. Immunoprecipitation experiments showed that Pf RBR‐E3 ligase catalyzes K6, K11, K48, and K63 mediated polyubiquitination, hinting towards its probable biological roles (DNA repair, proteasomal degradation, mitochondrial quality control). We observed that Pf RBR‐E3 ligase interacts with UBCH5 and UBC13 family of E2‐conjugating enzymes. Through mutational analysis in Pf RBR‐E3 ligase, we identified residues in RING1 and RING2 domains that are critical for ubiquitination activity and its protein stability. Pf RBR‐E3 ligase exhibits differences in immunofluorescence profile upon exposure of the parasite to different genotoxic (MMS) and proteotoxic (MG132, FCCP and artemisinin derivative) stress. Our study opens up avenues for exploring the client substrates of Pf RBR‐E3 ligase and using this knowledge to design substrate‐specific protein degradation‐based alternative intervention strategies for malaria. 10.1002/prot.26813 http://onlinelibrary.wiley.com/termsAndConditions#vor