Structural and Functional Insights into Human Nuclear Cyclophilins

Rajiv, Caroline; Davis, T.

doi:10.3390/biom8040161

Cited by 34 publications

(43 citation statements)

References 65 publications

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“…In hCyPH, N-terminal P8 is the primary residue interacting with the active-site R67 and H138 residues of a neighboring molecule by the formation of water-mediated H-bonds. Thus, in both hPPWD1 and hCyPH CyPs, the N-terminal proline residue plays a key role in interacting with active-site residues of an adjacent molecule, which is expected because both hPPWD1 and hCyPH have PPIase activities that in theory tend to interact with proline residue [56]. By contrast, in TvCyP2, the N-terminal P13 showed a hydrophobic contact with only Tyr93 of the S2 pocket but not with active-site residues.…”

Section: Discussionmentioning

confidence: 98%

N-Terminal Segment of TvCyP2 Cyclophilin from Trichomonas vaginalis Is Involved in Self-Association, Membrane Interaction, and Subcellular Localization

et al. 2020

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In Trichomonas vaginalis (T. vaginalis), cyclophilins play a vital role in dislodging Myb proteins from the membrane compartment and leading them to nuclear translocation. We previously reported that TvCyP1 cyclophilin from T. vaginalis forms a dimer and plays an essential role in moving the Myb1 transcription factor toward the nucleus. In comparison, TvCyP2 containing an extended segment at the N-terminus (N-terminal segment) formed a monomer and showed a different role in regulating protein trafficking. Four X-ray structures of TvCyP2 were determined under various conditions, all showing the N-terminal segment interacting with the active site of a neighboring TvCyP2, an unusual interaction. NMR study revealed that this particular interaction exists in solution as well and also the N-terminal segment seems to interact with the membrane. In vivo study of TvCyP2 and TvCyP2-∆N (TvCyP2 without the N-terminal segment) indicated that both proteins have different subcellular localization. Together, the structural and functional characteristics at the N-terminal segment offer valuable information for insights into the mechanism of how TvCyP2 regulates protein trafficking, which may be applied in drug development to prevent pathogenesis and disease progression in T. vaginalis infection.

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Section: Discussionmentioning

confidence: 98%

N-Terminal Segment of TvCyP2 Cyclophilin from Trichomonas vaginalis Is Involved in Self-Association, Membrane Interaction, and Subcellular Localization

et al. 2020

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“…Cyps are present in different compartments of the cell such as the cytosol, mitochondria, nucleus, or extracellular matrix in many different isoforms (Handschumacher et al, 1984;Rassow et al, 1995;Hoffmann and Schiene-Fischer, 2014;Rajiv et al, 2018). In Schistosoma mansoni, Kiang et al (1996) showed that cyclophilin is located in the tegument, muscle layers, intestinal epithelium, and interior of the worm, therefore, it is in contact with the host immune system.…”

Section: Introductionmentioning

confidence: 99%

The Schistosoma mansoni cyclophilin A epitope 107-121 induces a protective immune response against schistosomiasis

Melo¹,

Mendes²,

Alves³

et al. 2019

Molecular Immunology

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Great efforts have been made to identify promising antigens and vaccine formulations against schistosomiasis. Among the previously described Schistosoma vaccine candidates, cyclophilins comprise an interesting antigen that could be used for vaccine formulations. Cyclophilin A is the target for the cyclosporine A, a drug with schistosomicide activity, and its orthologue from Schistosoma japonicum induces a protective immune response in mice. Although Schistosoma mansoni cyclophilin A also represents a promising target for anti-schistosome vaccines, its potential to induce protection has not been evaluated. In this study, we characterized the cyclophilin A (SmCyp), initially described as Smp17.7, analyzed its allergenic potential using in vitro functional assays, and evaluated its ability to induce protection in mice when administered as an antigen using different vaccine formulations and strategies. Results indicated that SmCyp could be successfully expressed by mammalian cells and bacteria.The recombinant protein did not promote IgE-reporter system activation in vitro, demonstrating its probable safety for use in vaccine formulations. T and B-cell epitopes were predicted in the SmCyp sequence, with two of them located within the active isomerase site. The most immunogenic antigen, SmCyp (107-121), was then used for immunization protocols. Immunization with the SmCyp gene or protein failed to reduce parasite burden but induced an immune response that modulated the granuloma area. In contrast, immunization with the synthetic peptide SmCyp (107-121) significantly reduced worm burden (48-50%) in comparison to control group, but did not regulate liver pathology. Moreover, the protection observed in mice immunized with the synthetic peptide was associated with the significant production of antibodies against the SmCyp (107-121) epitope. Therefore, in this study, we identified an epitope within the SmCyp sequence that induces a protective immune response against the parasite, thus representing a promising antigen that could be used for vaccine formulation against schistosomiasis.

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“…Other upregulated genes are not well studied in the context of pancreatic endocrine development. PPIH is a component of the pre-mRNA processing complex and mediates pre-mRNA splicing (46). TMCC2 interacts with amyloid precursor protein and may play a role in neurodegeneration (47).…”

Section: Signatures Of the Neurog3+ Cellsmentioning

confidence: 99%

Gene Signatures of NEUROGENIN3+ Endocrine Progenitor Cells in the Human Pancreas

et al. 2021

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NEUROGENIN3+ (NEUROG3+) cells are considered to be pancreatic endocrine progenitors. Our current knowledge on the molecular program of NEUROG3+ cells in humans is largely extrapolated from studies in mice. We hypothesized that single-cell RNA-seq enables in-depth exploration of the rare NEUROG3+ cells directly in humans. We aligned four large single-cell RNA-seq datasets from postnatal human pancreas. Our integrated analysis revealed 10 NEUROG3+ epithelial cells from a total of 11,174 pancreatic cells. Noticeably, human NEUROG3+ cells clustered with mature pancreatic cells and epsilon cells displayed the highest frequency of NEUROG3 positivity. We confirmed the co-expression of NEUROG3 with endocrine markers and the high percentage of NEUROG3+ cells among epsilon cells at the protein level based on immunostaining on pancreatic tissue sections. We further identified unique genetic signatures of the NEUROG3+ cells. Regulatory network inference revealed novel transcription factors including Prospero homeobox protein 1 (PROX1) may act jointly with NEUROG3. As NEUROG3 plays a central role in endocrine differentiation, knowledge gained from our study will accelerate the development of beta cell regeneration therapies to treat diabetes.

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Structural and Functional Insights into Human Nuclear Cyclophilins

Cited by 34 publications

References 65 publications

N-Terminal Segment of TvCyP2 Cyclophilin from Trichomonas vaginalis Is Involved in Self-Association, Membrane Interaction, and Subcellular Localization

N-Terminal Segment of TvCyP2 Cyclophilin from Trichomonas vaginalis Is Involved in Self-Association, Membrane Interaction, and Subcellular Localization

The Schistosoma mansoni cyclophilin A epitope 107-121 induces a protective immune response against schistosomiasis

Gene Signatures of NEUROGENIN3+ Endocrine Progenitor Cells in the Human Pancreas

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