Overexpression, purification and assessment of cyclosporin binding of a family of cyclophilins and cyclophilin-like proteins of the human malarial parasite Plasmodium falciparum

Marín-Menéndez, Alejandro; Bell, Angus

doi:10.1016/j.pep.2011.04.012

Cited by 14 publications

(12 citation statements)

References 55 publications

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“…CsA is a cyclic hydrophobic undecapeptide that binds Cyclophilins and has been shown to possess significant anti-parasitic properties including anti-malarial activity both in vitro as well as in vivo 36 – 38 . Although the precise anti-malarial mode of action of CsA is not yet known, CsA has been proposed to bind Plasmodium -encoded Cyclophilins and Cyclophilin-like proteins 39 . To confirm the role of Cyclophilins in the merozoite invasion of RBCs, and to know whether CsA acts by blocking the interaction between CypB and PfRhopH3-C, we tested its inhibitory potential in an ELISA-based inhibition assay.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…2B), which is secreted extracellularly in response to oxidative stress and inflammation, where it acts as a growth factor for vascular smooth muscle and macrophages acting through ERK1/2 intracellular signaling both in an autocrine and paracrine fashion (38). Several cyclophilin and cyclophilin-like proteins of Plasmodium falciparum have been expressed recombinantly (39). Heat treatment of these proteins appears to ablate their ability to bind to CsA, indicative of changes in protein conformation.…”

Section: Discussionmentioning

confidence: 99%

Secreted Trypanosome Cyclophilin Inactivates Lytic Insect Defense Peptides and Induces Parasite Calcineurin Activation and Infectivity

Kulkarni

Karafova

Kamysz

et al. 2013

Journal of Biological Chemistry

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Background:The mechanisms of insect immune peptide recognition and evasion by T. cruzi are unknown. Results: Secreted parasite cyclophilin neutralizes lytic peptide, causes activation of parasite calcineurin, and enhances parasite infection. Conclusion: Cyclophilin is a key mediator of antimicrobial peptide evasion and triggers parasite calcineurin signaling. Significance: The cyclophilin-calcineurin pathway is an extracellular peptide microbial-host sensing mechanism.

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“…For example, 8 of the 11 putative cyclophilins and cyclophilin-like proteins of P. falciparum were analyzed after recombinant production. Only two of those, P. falciparum Cyp19A (PfCyp19A) and PfCyp19B, bound CsA and displayed in vitro PPIase activity, while all had chaperone functions preventing thermal aggregation of the model protein substrates rhodanese and citrate synthase (98,99). This alone can be taken as an indication of the unexplored functional diversity of cyclophilins in parasitic protozoa, depending on their developmental or infection cycle stage.…”

Section: Ppiases Of Parasitic Protozoamentioning

confidence: 99%

Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

Ünal

Steinert

2014

Microbiol Mol Biol Rev

160

146

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SUMMARY Initially discovered in the context of immunomodulation, peptidyl-prolyl cis/trans isomerases (PPIases) were soon identified as enzymes catalyzing the rate-limiting protein folding step at peptidyl bonds preceding proline residues. Intense searches revealed that PPIases are a superfamily of proteins consisting of three structurally distinguishable families with representatives in every described species of prokaryote and eukaryote and, recently, even in some giant viruses. Despite the clear-cut enzymatic activity and ubiquitous distribution of PPIases, reports on solely PPIase-dependent biological roles remain scarce. Nevertheless, they have been found to be involved in a plethora of biological processes, such as gene expression, signal transduction, protein secretion, development, and tissue regeneration, underscoring their general importance. Hence, it is not surprising that PPIases have also been identified as virulence-associated proteins. The extent of contribution to virulence is highly variable and dependent on the pleiotropic roles of a single PPIase in the respective pathogen. The main objective of this review is to discuss this variety in virulence-related bacterial and protozoan PPIases as well as the involvement of host PPIases in infectious processes. Moreover, a special focus is given to Legionella pneumophila macrophage infectivity potentiator (Mip) and Mip-like PPIases of other pathogens, as the best-characterized virulence-related representatives of this family. Finally, the potential of PPIases as alternative drug targets and first tangible results are highlighted.

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Overexpression, purification and assessment of cyclosporin binding of a family of cyclophilins and cyclophilin-like proteins of the human malarial parasite Plasmodium falciparum

Cited by 14 publications

References 55 publications

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

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

Secreted Trypanosome Cyclophilin Inactivates Lytic Insect Defense Peptides and Induces Parasite Calcineurin Activation and Infectivity

Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

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