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As important components of cellular redox biology, members of the Thioredoxin (Trx) superfamily of proteins have received interest as potential drug targets in Apicomplexans. However, the function and essentiality of endoplasmic reticulum (ER)-localized Trx-domain proteins within\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    has not been investigated. We generated conditional mutants of the protein\n                    <jats:italic>Pf<\/jats:italic>\n                    J2\u2014an ER chaperone and member of the Trx superfamily\u2014and show that it is essential for asexual parasite survival. Using a crosslinker specific for redox-active cysteines, we identified\n                    <jats:italic>Pf<\/jats:italic>\n                    J2 substrates as\n                    <jats:italic>Pf<\/jats:italic>\n                    PDI8 and\n                    <jats:italic>Pf<\/jats:italic>\n                    PDI11, both members of the Trx superfamily as well, which suggests a redox-regulatory role for\n                    <jats:italic>Pf<\/jats:italic>\n                    J2. Knockdown of these PDIs in\n                    <jats:italic>Pf<\/jats:italic>\n                    J2 conditional mutants show that\n                    <jats:italic>Pf<\/jats:italic>\n                    PDI11 may not be essential. However,\n                    <jats:italic>Pf<\/jats:italic>\n                    PDI8 is required for asexual growth and our data suggest it may work in a complex with\n                    <jats:italic>Pf<\/jats:italic>\n                    J2 and other ER chaperones. Finally, we show that the redox interactions between these Trx-domain proteins in the parasite ER and their substrates are sensitive to small molecule inhibition. Together these data build a model for how Trx-domain proteins in the\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    ER work together to assist protein folding and demonstrate the suitability of ER-localized Trx-domain proteins for antimalarial drug development.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009293","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T14:34:46Z","timestamp":1612362886000},"page":"e1009293","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["A redox-active crosslinker reveals an essential and inhibitable oxidative folding network in the endoplasmic reticulum of malaria parasites"],"prefix":"10.1371","volume":"17","author":[{"given":"David W.","family":"Cobb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"Kudyba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6223-3203","authenticated-orcid":true,"given":"Alejandra","family":"Villegas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7029-7792","authenticated-orcid":true,"given":"Michael R.","family":"Hoopmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1806-8260","authenticated-orcid":true,"given":"Rodrigo P.","family":"Baptista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3473-4569","authenticated-orcid":true,"given":"Baylee","family":"Bruton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1888-5869","authenticated-orcid":true,"given":"Michelle","family":"Krakowiak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3216-9447","authenticated-orcid":true,"given":"Robert L.","family":"Moritz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6367-6284","authenticated-orcid":true,"given":"Vasant","family":"Muralidharan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,3]]},"reference":[{"key":"ppat.1009293.ref001","unstructured":"World Heath Organization C. 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