Abstract
Peroxiredoxins (Prxs) are crucially involved in maintaining intracellular H2O2 homeostasis via their peroxidase activity. However, more recently, this class of proteins was found to also transmit oxidizing equivalents to selected downstream proteins, which suggests an important function of Prxs in the regulation of cellular protein redox relays. Using a pull-down assay based on mixed disulfide fishing, we characterized the thiol-dependent interactome of cytosolic Prx1a and mitochondrial Prx1m from the apicomplexan malaria parasite Plasmodium falciparum (Pf). Here, 127 cytosolic and 20 mitochondrial proteins that are components of essential cellular processes were found to interact with PfPrx1a and PfPrx1m, respectively. Notably, our data obtained with active-site mutants suggests that reducing equivalents might also be transferred from Prxs to target proteins. Initial functional analyses indicated that the interaction with Prx can strongly impact the activity of target proteins. The results provide initial insights into the interactome of Prxs at the level of a eukaryotic whole cell proteome. Furthermore, they contribute to our understanding of redox regulatory principles and thiol-dependent redox relays of Prxs in subcellular compartments.
Highlights
Research on peroxiredoxins (Prxs) has expanded rapidly in recent years[1]
The Prx is in the fully folded (FF) conformation and starts a nucleophilic attack at the peroxyl bond of the hydroperoxide substrate (ROOH), whereby the thiolate is oxidized to a sulfenic acid (SOH), and an alcohol is released
The Prx switches its conformation from the FF to the locally unfolded (LU) conformation, and the CR is able to form a disulfide bond with the CP, which is intermolecular in the typical 2-Cys Prxs and intramolecular in the atypical 2-Cys Prxs
Summary
Research on peroxiredoxins (Prxs) has expanded rapidly in recent years[1]. After initial discovery in human erythrocytes[2,3], Prxs—as cysteine-dependent peroxidases and sensor transducers—were described in all kingdoms of life including protozoal parasites such as Toxoplasma, Trypanosoma, Leishmania, and Plasmodium[4,5]. 1.11.1.15) are ubiquitous cysteine-dependent peroxidases and can regulate the intracellular messenger function of H2O2. They are able to reduce endogenous and exogenous H2O2, peroxynitrite (ONOO−), and organic hydroperoxides (ROOH)[6], and their recycling depends on redoxins such as thioredoxin (Trx) or glutaredoxin (Grx). Prxs can be found in the cytosol, mitochondria, nucleus, and even plastids They can interact with and inhibit the function of certain oncoproteins[8,9], can enhance the toxic effect of natural killer cells[10], maintain genome stability, promote longevity[11], and can be induced by proliferative stimuli[12], nitric oxide[13], and oxidative stress[14]. P. falciparum possesses five peroxiredoxins, which support www.nature.com/scientificreports/
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