ArticleInfection and immunity2015
A CLAG3 mutation in an amphipathic transmembrane domain alters malaria parasite nutrient channels and confers leupeptin resistance.
Article in Infection and immunity, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 32 citations in OpenAlex.
- Physiological febrile heat stress increases cytoadhesion through increased protein trafficking ofeLife · 2026Article
- Article
- The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels.Cell chemical biology · 2025Article
- A High-Throughput Inhibitor Screen Targeting CLAG3 Export and Membrane Insertion on Human Erythrocytes Infected with Malaria Parasites.Pathogens (Basel, Switzerland) · 2025Article
- Utilisation of an in vivo malaria model to provide functional proof for RhopH1/CLAG essentiality and conserved orthology with P. falciparum.Journal of biomedical science · 2025Article
- Novel Ion Channel Genes in Malaria Parasites.Genes · 2024Review
- Unique Properties of Nutrient Channels onPathogens (Basel, Switzerland) · 2023Review
- Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads.Molecular pharmacology · 2022Article
- Epigenetics of malaria parasite nutrient uptake, but why?Trends in parasitology · 2022Review
- Article
- RhopH2 and RhopH3 export enables assembly of the RhopH complex on P. falciparum-infected erythrocyte membranes.Communications biology · 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
- Promises and Pitfalls of Parasite Patch-clamp.Trends in parasitology · 2021Review
- Article
- How Malaria Parasites Acquire Nutrients From Their Host.Frontiers in cell and developmental biology · 2021Review
- A Histone Methyltransferase Inhibitor Can Reverse Epigenetically Acquired Drug Resistance in the Malaria Parasite Plasmodium falciparum.Antimicrobial agents and chemotherapy · 2020Article
- Complex nutrient channel phenotypes despite Mendelian inheritance in a Plasmodium falciparum genetic cross.PLoS pathogens · 2020Article
- A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4.Scientific reports · 2019Article
- Diverse target gene modifications in Plasmodium falciparum using Bxb1 integrase and an intronic attB.Parasites & vectors · 2018Review
- Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Erythrocytes infected with malaria parasites have increased permeability to ions and nutrients, as mediated by the plasmodial surface anion channel (PSAC) and recently linked to parasite clag3 genes. Although the encoded protein is integral to the host membrane, its precise contribution to solute transport remains unclear because it lacks conventional transmembrane domains and does not have homology to ion channel proteins in other organisms. Here, we identified a probable CLAG3 transmembrane domain adjacent to a variant extracellular motif. Helical-wheel analysis revealed strict segregation of polar and hydrophobic residues to opposite faces of a predicted α-helical transmembrane domain, suggesting that the domain lines a water-filled pore. A single CLAG3 mutation (A1210T) in a leupeptin-resistant PSAC mutant falls within this transmembrane domain and may affect pore structure. Allelic-exchange transfection and site-directed mutagenesis revealed that this mutation alters solute selectivity in the channel. The A1210T mutation also reduces the blocking affinity of PSAC inhibitors that bind on opposite channel faces, consistent with global changes in channel structure. Transfected parasites carrying this mutation survived a leupeptin challenge significantly better than a transfection control did. Thus, the A1210T mutation contributes directly to both altered PSAC activity and leupeptin resistance. These findings reveal the molecular basis of a novel antimalarial drug resistance mechanism, provide a framework for determining the channel's composition and structure, and should guide the development of therapies targeting the PSAC.
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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.