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Nedd8 hydrolysis by UCH proteases in Plasmodium parasites.
Karpiyevich, Maryia; Adjalley, Sophie; Mol, Marco; Ascher, David B; Mason, Bethany; van der Heden van Noort, Gerbrand J; Laman, Heike; Ovaa, Huib; Lee, Marcus C S; Artavanis-Tsakonas, Katerina.
Afiliación
  • Karpiyevich M; Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
  • Adjalley S; Parasites and Microbes Programme, Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Mol M; Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
  • Ascher DB; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
  • Mason B; Department of Biochemistry, University of Melbourne, Melbourne, Australia.
  • van der Heden van Noort GJ; Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
  • Laman H; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands.
  • Ovaa H; Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
  • Lee MCS; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands.
  • Artavanis-Tsakonas K; Parasites and Microbes Programme, Wellcome Sanger Institute, Cambridge, United Kingdom.
PLoS Pathog ; 15(10): e1008086, 2019 10.
Article en En | MEDLINE | ID: mdl-31658303
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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Plasmodium falciparum / Ubiquitina Tiolesterasa / Ubiquitina-Proteína Ligasas / Proteína NEDD8 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: PLoS Pathog Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Plasmodium falciparum / Ubiquitina Tiolesterasa / Ubiquitina-Proteína Ligasas / Proteína NEDD8 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: PLoS Pathog Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido