Immunophilin–protein interactions in<i>Plasmodium falciparum</i>

Leneghan, Darren B.; Bell, Angus

doi:10.1017/s0031182015000803

Cited by 17 publications

(21 citation statements)

References 37 publications

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“…The compounds chosen included CsA, the standard antimalarial drugs artemisinin and chloroquine, the Hsp90 inhibitor geldanamycin and the Hsp70 inhibitor pifithrin- μ . We choose the last two because both heat-shock proteins interact with PfFKBP35 (Kumar et al 2005; Leneghan & Bell, 2015) and there was a possibility that this might lead to interactions of Hsp90 or Hsp70 inhibitors with FK506 and/or Rap. Pifithrin- μ had not previously been tested on Plasmodium but we found it to be antimalarial in culture with an IC 50 of 15 µ m .…”

Section: Resultsmentioning

confidence: 99%

“…The function of PfFKBP35 can be guessed at based on data from FKBPs of other organisms (Bell et al 2006) – we expect it to be involved in folding, transport and/or regulation of other proteins and perhaps in the response to stresses such as the temperature shocks encountered on transfer between hosts (Acharya et al 2007). Its interacting partner proteins are now known to include heat-shock proteins and histones (Leneghan & Bell, 2015) but the physiological/biochemical consequences of these molecular interactions have not yet been extensively investigated. In this paper, we have shown that the pharmacodynamic actions of two PfFKBP35 ligands, FK506 and Rap, were essentially indistinguishable.…”

Section: Discussionmentioning

confidence: 99%

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The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35

et al. 2017

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FK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506-FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap -FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement of Plasmodium calcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of the Plasmodium falciparum FKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35

et al. 2017

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“…Cyclophilins belong to the immunophilin class of proteins 18 and some members of this family have been associated with parasitic diseases. Human malaria parasite P. falciparum encodes 13 immunophilins or immunophilin-like proteins; however, their exact functions are still unknown 19 – 21 .…”

Section: Introductionmentioning

confidence: 99%

Human Cyclophilin B forms part of a multi-protein complex during erythrocyte invasion by Plasmodium falciparum

et al. 2017

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Invasion of human erythrocytes by Plasmodium falciparum merozoites involves multiple interactions between host receptors and their merozoite ligands. Here we report human Cyclophilin B as a receptor for PfRhopH3 during merozoite invasion. Localization and binding studies show that Cyclophilin B is present on the erythrocytes and binds strongly to merozoites. We demonstrate that PfRhopH3 binds to the RBCs and their treatment with Cyclosporin A prevents merozoite invasion. We also show a multi-protein complex involving Cyclophilin B and Basigin, as well as PfRhopH3 and PfRh5 that aids the invasion. Furthermore, we report identification of a de novo peptide CDP3 that binds Cyclophilin B and blocks invasion by up to 80%. Collectively, our data provide evidence of compounded interactions between host receptors and merozoite surface proteins and paves the way for developing peptide and small-molecules that inhibit the protein−protein interactions, individually or in toto, leading to abrogation of the invasion process.

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“…PF3D7_0604500 encodes a protein containing a GYF domain, which recognizes the proline-rich sequence. It was found to interact with PfCYP19A, a peptidyl-prolyl cistrans isomerase in P. falciparum [321].…”

Section: Common Interacting Partners Of Caf1 and Not4mentioning

confidence: 99%

Investigation of NOT1 proteins in regulating gene expression in plasmodium falciparum

Liu¹

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Plasmodium falciparum is the most deadly form of malaria that threatens millions of people around the world. The CCR4-NOT complex is a highly conserved complex that regulates gene expression across the eukaryotic kingdom and NOT1 is the scaffold of the complex. P. falciparum encodes two paralogs of NOT1, NOT1.1 (PF3D7_1103800) and NOT1.2 (PF3D7_1417200). My study investigates the function of two NOT1 proteins in gene regulation during the 48-hour intraerythrocytic developmental cycle.I found that NOT1.1 and NOT1.2 are probably the scaffold of the complex in P. falciparum, interacting with CAF1, CCR4, CAF40 as well as NOT4 subunits. The independent mutation of Not1.1 and Not1.2 leads to altered mRNA abundance of many genes, including many egress-and invasion-related genes, which may result in defective growth and invasion rate. The knockout of Not1.1 affects recruitment of the elongating form of RNA Polymerase II, which however is not significantly correlated to differential mRNA abundance, suggesting the role of NOT1.1 in post-transcriptional regulation. In addition, comparison between the differential mRNA abundance in the two mutants reveals a negative correlation, demonstrating opposite functions of NOT1.1 and NOT1.2 in gene regulation. Furthermore, I found that differential mRNA abundance in the two mutants is correlated to that in Caf1 mutant and Alba1 mutant.I propose that NOT1.1 and NOT1.2 compete to be the scaffold of the CCR4-NOT complex and regulate gene expression post-transcriptionally by modulating the functions of their interacting proteins, including CAF1 and ALBA1, which are key players in mRNA metabolism. List of AbbreviationsAbbreviation Name 5-FC 5-fluorocytosine ACT Artemisinin-based combination therapy ALBA Acetylation lowers binding affinity AMA1 Apical membrane antigen-1 Bam Bag-of-marbles CDPK5 Calcium-dependent protein kinase 5 CELF CUG-BP, Elav-like family ChIP Chromatin-immunoprecipitation CITH CAR-I/Trailer Hitch Homolog CK2β2 Casein kinase II beta chain-2 CPSF3 Cleavage and polyadenylation specificity factor-3 CTD C-terminal domain of RPB1

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Immunophilin–protein interactions inPlasmodium falciparum

Abstract: SUMMARY 24Immunophilins comprise two protein families, cyclophilins (CYPs) and FK506-binding 47• PfCYP19B interacts specifically with PfHsp70. 48• Cyclophilin ligands disrupt transport of RAP1 in cultured parasites. 49

Cited by 17 publications

References 37 publications

The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35

The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35

Human Cyclophilin B forms part of a multi-protein complex during erythrocyte invasion by Plasmodium falciparum

Investigation of NOT1 proteins in regulating gene expression in plasmodium falciparum

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