ArticlePLoS pathogens2021
A redox-active crosslinker reveals an essential and inhibitable oxidative folding network in the endoplasmic reticulum of malaria parasites.
Article in PLoS pathogens, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 14 citations in OpenAlex.
- Disulphide maintenance systems and proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- The long and winding road: On the endoplasmic reticulum of Plasmodium and implications for pathogenesis.PLoS pathogens · 2026Review
- Article
- Deciphering Membrane Protein Complexes in Plasmodium falciparum Gametocytes via Integrative Structural Systems Biology.Molecular & cellular proteomics : MCP · 2026Article
- The J Domain Proteins ofInternational journal of molecular sciences · 2024Review
- Article
- Knock-sideways by inducible ER retrieval enables a unique approach for studyingProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Identifying Interaction Partners of Yeast Protein Disulfide Isomerases Using a Small Thiol-Reactive Cross-Linker: Implications for Secretory Pathway Proteostasis.Chemical research in toxicology · 2022Article
- Activity-based Crosslinking to Identify Substrates of Thioredoxin-domain Proteinsin Malaria Parasites.Bio-protocol · 2022Article
- Native structure of the RhopH complex, a key determinant of malaria parasite nutrient acquisition.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Dnj1 Promotes Virulence inFrontiers in microbiology · 2021Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Malaria remains a major global health problem, creating a constant need for research to identify druggable weaknesses in P. falciparum biology. 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 P. falciparum has not been investigated. We generated conditional mutants of the protein PfJ2-an ER chaperone and member of the Trx superfamily-and show that it is essential for asexual parasite survival. Using a crosslinker specific for redox-active cysteines, we identified PfJ2 substrates as PfPDI8 and PfPDI11, both members of the Trx superfamily as well, which suggests a redox-regulatory role for PfJ2. Knockdown of these PDIs in PfJ2 conditional mutants show that PfPDI11 may not be essential. However, PfPDI8 is required for asexual growth and our data suggest it may work in a complex with PfJ2 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 P. falciparum ER work together to assist protein folding and demonstrate the suitability of ER-localized Trx-domain proteins for antimalarial drug development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.