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dc.contributor.authorArtavanis-Tsakonas, Katerinaen
dc.contributor.authorKarpiyevich, Maryiaen
dc.contributor.authorAdjalley, Sophieen
dc.contributor.authorMol, Marcoen
dc.contributor.authorAscher, Daviden
dc.contributor.authorMason, Bethanyen
dc.contributor.authorvan der Heden van Noort, Gerbranden
dc.contributor.authorLaman, Heikeen
dc.contributor.authorOvaa, Huiben
dc.contributor.authorLee, Marcus CSen
dc.date.accessioned2019-12-07T00:30:12Z
dc.date.available2019-12-07T00:30:12Z
dc.identifier.issn1553-7366
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/299608
dc.description.abstractPlasmodium 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.
dc.description.sponsorshipIncludes Wellcome and BBSRC.
dc.publisherPublic Library of Science (PLoS)
dc.relation.isreplacedby1810/311340
dc.relation.isreplacedbyhttps://www.repository.cam.ac.uk/handle/1810/311340
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleNedd8 hydrolysis by UCH proteases in Plasmodium parasitesen
dc.typeArticle
prism.issueIdentifier10en
prism.numbere1008086en
prism.publicationNamePLoS Pathogensen
prism.volume15en
dc.identifier.doi10.17863/CAM.46680
dcterms.dateAccepted2019-09-16en
rioxxterms.versionofrecord10.1371/journal.ppat.1008086en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-09-16en
dc.contributor.orcidAscher, David [0000-0003-2948-2413]
dc.contributor.orcidLaman, Heike [0000-0002-6089-171X]
dc.identifier.eissn1553-7374
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBBSRC (BB/R001642/1)
pubs.funder-project-idBreast Cancer Campaign (2013NovPhD172)
pubs.funder-project-idMRC (MR/M026302/1)
pubs.funder-project-idBreast Cancer Now (2013NovPhD172)
cam.issuedOnline2019-10-28en


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International