Nedd8 hydrolysis by UCH proteases in Plasmodium parasites

Autoři: Maryia Karpiyevich aff001;  Sophie Adjalley aff002;  Marco Mol aff001;  David B. Ascher aff003;  Bethany Mason aff001;  Gerbrand J. van der Heden van Noort aff005;  Heike Laman aff001;  Huib Ovaa aff005;  Marcus C. S. Lee aff002;  Katerina Artavanis-Tsakonas aff001
Působiště autorů: Department of Pathology, University of Cambridge, Cambridge, United Kingdom aff001;  Parasites and Microbes Programme, Wellcome Sanger Institute, Cambridge, United Kingdom aff002;  Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom aff003;  Department of Biochemistry, University of Melbourne, Melbourne, Australia aff004;  Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands aff005
Vyšlo v časopise: Nedd8 hydrolysis by UCH proteases in Plasmodium parasites. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1008086
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008086


Plasmodium parasites are the causative agents of malaria, a disease with wide public health repercussions. Increasing drug resistance and the absence of a vaccine make finding new chemotherapeutic strategies imperative. Components of the ubiquitin and ubiquitin-like pathways have garnered increased attention as novel targets given their necessity to parasite survival. Understanding how these pathways are regulated in Plasmodium and identifying differences to the host is paramount to selectively interfering with parasites. Here, we focus on Nedd8 modification in Plasmodium falciparum, given its central role to cell division and DNA repair, processes critical to Plasmodium parasites given their unusual cell cycle and requirement for refined repair mechanisms. By applying a functional chemical approach, we show that deNeddylation is controlled by a different set of enzymes in the parasite versus the human host. We elucidate the molecular determinants of the unusual dual ubiquitin/Nedd8 recognition by the essential PfUCH37 enzyme and, through parasite transgenics and drug assays, determine that only its ubiquitin activity is critical to parasite survival. Our experiments reveal interesting evolutionary differences in how neddylation is controlled in higher versus lower eukaryotes, and highlight the Nedd8 pathway as worthy of further exploration for therapeutic targeting in antimalarial drug design.

Klíčová slova:

Crystal structure – Enzymes – Hydrolysis – Malarial parasites – Parasitic diseases – Plasmodium – Plasmodium falciparum – Proteasomes


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