Structural and Functional Characterization of a Novel Family of Cyclophilins, the AquaCyps

Jakob, R.P.; Schmidpeter, Philipp A. M.; Koch, Johanna R.; Schmid, Franz X.; Maier, Timm

doi:10.1371/journal.pone.0157070

Cited by 8 publications

(5 citation statements)

References 79 publications

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“…Considering Cyps from other organisms, variability in kinetic parameters was observed for the two TgCyps. Indeed, the catalytic efficiency of TgCyp23 for the AAPF peptide substrate was high ( k cat / K m = 2.89 × 10 6 M –1 s –1 ) and resembled that of human CypA and some other Cyps, − implying that TgCyp23 is a highly active PPIase. On the contrary, TgCyp18.4 is also active as a PPIase but differs significantly from TgCyp23 and human CypA.…”

Section: Resultsmentioning

confidence: 96%

Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii

et al. 2023

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Cyclosporin (CsA) has antiparasite activity against the human pathogen Toxoplasma gondii. A possible mechanism of action involves CsA binding to T. gondii cyclophilins, although much remains to be understood. Herein, we characterize the functional and structural properties of a conserved (TgCyp23) and a more divergent (TgCyp18.4) cyclophilin isoform from T. gondii. While TgCyp23 is a highly active cis–trans-prolyl isomerase (PPIase) and binds CsA with nanomolar affinity, TgCyp18.4 shows low PPIase activity and is significantly less sensitive to CsA inhibition. The crystal structure of the TgCyp23:CsA complex was solved at the atomic resolution showing the molecular details of CsA recognition by the protein. Computational and structural studies revealed relevant differences at the CsA-binding site between TgCyp18.4 and TgCyp23, suggesting that the two cyclophilins might have distinct functions in the parasite. These studies highlight the extensive diversification of TgCyps and pave the way for antiparasite interventions based on selective targeting of cyclophilins.

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Section: Resultsmentioning

confidence: 96%

Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii

et al. 2023

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“…Since it was reported that PPIases can form homo-oligomers ( Budiman et al, 2009 ; Zhang et al, 2011 ; Jakob et al, 2016 ; Polley et al, 2016 ) we studied the possibility that CypA and CypB were able to oligomerize. As shown in Figure 7A , when we subjected CypA or CypB to SDS-PAGE and Western blot analysis, a single protein band corresponding to the recombinant CypA or CypB was detected as expected for the monomeric form of these cyclophilins.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that PPIases can form homo-oligomers ( Zhang et al, 2011 ; Jakob et al, 2016 ; Polley et al, 2016 ) although, in the family of cyclophilins, only a few cases have been reported: the human hCypA ( Zhang et al, 2011 ) and the Trichomonas vaginalis cyclophilin 1 ( Martin et al, 2018 ). In addition, in the case of dimeric PPIases, no homodimer formation has been reported dependent on disulfide bonds.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, even though single-domain cyclophilins are devoid of a canonical chaperone protein domain they can still present certain chaperone activity, which in some cases it has been shown to be independent of the PPIase catalytic activity ( Dimou et al, 2011 ; Zhang et al, 2013 ; Pandey et al, 2016 ). Moreover, it has been described that some of the single-domain cyclophilins are still able to oligomerize ( Zhang et al, 2011 ; Jakob et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Biochemical and functional characterization of Brucella abortus cyclophilins: So similar, yet so different

Muruaga

Briones²,

Roset³

2022

Front. Microbiol.

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Brucella spp. are the etiological agent of animal and human brucellosis. We have reported previously that cyclophilins of Brucella (CypA and CypB) are upregulated within the intraphagosomal replicative niche and required for stress adaptation and host intracellular survival and virulence. Here, we characterize B. abortus cyclophilins, CypA, and CypB from a biochemical standpoint by studying their PPIase activity, chaperone activity, and oligomer formation. Even though CypA and CypB are very similar in sequence and share identical chaperone and PPIase activities, we were able to identify outstanding differential features between them. A series of differential peptide loops were predicted when comparing CypA and CypB, differences that might explain why specific antibodies (anti-CypA or anti-CypB) were able to discriminate between both cyclophilins without cross-reactivity. In addition, we identified the presence of critical amino acids in CypB, such as the Trp134 which is responsible for the cyclosporin A inhibition, and the Cys128 that leads to CypB homodimer formation by establishing a disulfide bond. Here, we demonstrated that CypB dimer formation was fully required for stress adaptation, survival within HeLa cells, and mouse infection in B. abortus. The presence of Trp134 and the Cys128 in CypB, which are not present in CypA, suggested that two different kinds of cyclophilins have evolved in Brucella, one with eukaryotic features (CypB), another (CypA) with similar features to Gram-negative cyclophilins.

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“…Degradation of organic matter and hydrocarbons [49] Denitrification [50] Secretion of extracellular proteins and biofilm formation [51] Caulobacteraceae Caulobacter Secretion of extracellular polymers [50] Adapts to and may be able to degrade triclosan (TCS) […”

Section: Family Genus Environmental Functionsmentioning

confidence: 99%

Effect and Mechanism of Applying Myriophyllum Verticillatum for Reclaimed Water Purification in Urban Rivers

Zhu

Lin

et al. 2023

Water

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Reclaimed water produced via the advanced treatment of domestic wastewater has broad application prospects for reuse in urban rivers, while the nutrients in reclaimed water, especially nitrogen and phosphorus, lead to eutrophication or ecological impacts. Submerged plants are preferred as an enhanced technology used at reclaimed water recharge sites for both water quality improvement purposes and ecological conservation functions. In this study, which adopted the typical submerged plant Myriophyllum verticillatum (M. verticillatum) as its experimental object, experiments were carried out in an illumination incubator without a substrate and under hydrostatic conditions to investigate the water purification effects and mechanisms of action of M. verticillatum at different planting densities. The analysis showed that the group with a wet weight of 2.5 g L−1 had the best growth status and the best overall performance with respect to improvements in water quality indicators, including COD, nitrogen, and phosphorus, as well as demonstrating excellent uptake and synergistic effects in the process of removing nitrogen and phosphorus. The contributions of natural effects, the uptake and enrichment by M. verticillatum itself, and the synergistic effects during the nitrogen and phosphorus removal process were quantified. Furthermore, 16S rRNA gene sequencing was used to determine the surface-attached bacterial colonies of M. verticillatum, to analyze their population diversity, and to identify environmental functional genera. In conclusion, an appropriate density of M. verticillatum can improve water quality and provide a suitable environment for the survival and growth of relevant environmentally functional microorganisms, effectively removing nitrogen and phosphorus through its own absorption and synergistic effects.

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Structural and Functional Characterization of a Novel Family of Cyclophilins, the AquaCyps

Cited by 8 publications

References 79 publications

Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii

Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii

Biochemical and functional characterization of Brucella abortus cyclophilins: So similar, yet so different

Effect and Mechanism of Applying Myriophyllum Verticillatum for Reclaimed Water Purification in Urban Rivers

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