Disease relevance of PPIB

• Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase [1].
• The binding site for cyclophilin A, a cellular rotamase that is packaged into the HIV-1 virion, is located on the exposed loop and encompasses the essential proline residue Pro90 [2].
• Escherichia coli cyclophilin B binds a highly distorted form of trans-prolyl peptide isomer [3].
• Cyclophilin B escorts the hepatitis C virus RNA polymerase: a viral achilles heel [4]?
• HLA-A24-restricted and tumor-specific CTLs established from T cells infiltrating into lung adenocarcinoma recognized the two antigenic peptides encoded by a cyclophilin B gene, a family of genes for cyclophilins involved in T cell activation [5].

High impact information on PPIB

• CAML appears to be a new participant in the calcium-signal transduction pathway, implicating cyclophilin B in calcium signalling, even in the absence of cyclosporin [6].
• Calcium signalling in T cells stimulated by a cyclophilin B-binding protein [6].
• Both the RNA interference (RNAi)-mediated reduction of endogenous CyPB expression and the induced loss of NS5B binding to CyPB decreased the levels of HCV replication [1].
• Interaction with glycosaminoglycans is required for cyclophilin B to trigger integrin-mediated adhesion of peripheral blood T lymphocytes to extracellular matrix [7].
• Pin1 contains an N-terminal WW domain and a C-terminal peptidyl-prolyl cis-trans isomerase (PPIase) domain connected by a flexible linker [8].

Chemical compound and disease context of PPIB

• The crystal structures analyzed in this study show two complexes in which peptides having a trans-form proline, i.e. succinyl-Ala-trans-Pro-Ala-p-nitroanilide and acetyl-Ala-Ala-trans-Pro-Ala-amidomethylcoumarin, are bound on a K163T mutant of Escherichia coli cyclophilin B, the preprotein of which has a signal sequence [3].

Biological context of PPIB

• Cyclophilin B (CyPB), a cyclosporin A (CsA) binding protein, interacts with two types of binding sites at the surface of T-lymphocytes [9].
• Because both groups of drugs inhibit the rotamase activity of cyclophilins (CyP), but only the immunosuppressant analogs inhibit calcineurin activity, these data suggest that rotamase inhibition underlies the enhanced cell death after SODV148G expression [10].
• Cyclophilin B has been shown previously to be located within calcium-containing intracellular vesicles; its ability to mediate CsA inhibition implies that certain components of the signal transduction machinery are also spatially restricted within the cell [11].
• The catalytic site of cyclophilin B therefore did not seem to be essential for cellular binding and the cyclosporin A binding site appeared to be partially involved in the binding to type I sites [12].
• Competitive binding experiments using a chimaeric protein made up of the 24 N-terminal amino acid residues of CyPB fused to the cyclophilin A core sequence confirmed the involvement of this region of CyPB in receptor binding [13].

Anatomical context of PPIB

• By contrast, cyclophilin B (CPH-B) has a punctuate and reticular distribution pattern in cytoplasm, indicating an association with the endoplasmatic reticulum, but its main location is in the nuclear matrix, sparing the nucleolar region [14].
• A yeast two-hybrid screen identified an interaction between PRL and cyclophilin B (CypB), a peptidyl prolyl isomerase (PPI) found in the endoplasmic reticulum (ER), extracellular space, and nucleus [15].
• Cyclophilin B is targeted to the secretory pathway via an endoplasmic reticulum signal sequence [16].
• We suggest that cyclosporin A competes with endogenous plasma membrane proteins for association with cyclophilin B in the secretory pathway [16].
• In this study, we intended to characterize the areas of cyclophilin B involved in the interactions with binding sites present on Jurkat cells [12].

Associations of PPIB with chemical compounds

• To identify potential cellular homologues of cyclosporin A that might regulate calcium signalling, we have cloned human genes encoding cyclophilin B-binding-proteins using the yeast two-hybrid system [6].
• The higher potency of the CypB/CsA complex versus CypA/CsA in inhibiting the Ca(2+)- and calmodulin-dependent protein phosphatase calcineurin is discussed in terms of the structural differences between the two complexes [17].
• Mutational analysis of CyPB has revealed that W128, which is part of the CsA-binding pocket, is implicated in the binding to the functional type I receptors and that two amino acid clusters located in the N-terminus ensure the binding to GAGs [9].
• Sequencing of this protein revealed identity of the NH2-terminal amino acids with those of human cyclophilin A. The finding is unexpected since cyclophilin B rather than A is generally regarded as the secreted isoform, the presence of cyclophilin A being confined to the cytoplasm [18].
• These findings argue in favor of a role for cyclophilin B as a chaperone to proteins destined for the plasma membrane, rather than solely as a proline isomerase functioning within the endoplasmic reticulum [16].

Other interactions of PPIB

• X-ray structure of a cyclophilin B/cyclosporin complex: comparison with cyclophilin A and delineation of its calcineurin-binding domain [17].
• The potentiation of PRL action by CypB was accompanied by a dramatic increase in the nuclear retrotranslocation of PRL [15].
• Receptor type I and type II binding regions and the peptidyl-prolyl isomerase site of cyclophilin B are required for enhancement of T-lymphocyte adhesion to fibronectin [9].
• Role of cyclophilin B in activation of interferon regulatory factor-3 [19].
• Although etiolated leaves produced detectable levels of cyclophilin B/C, they did not express FKBP13 [20].

Analytical, diagnostic and therapeutic context of PPIB

• Amplification of the target gene in the duplex NASBA assay was disrupted when this latter was mixed with a large amount of the housekeeping PPIB gene, suggesting that it is preferable for the normalizing gene chosen to have an expression level comparable to the target gene [21].
• Using surface plasmon resonance spectroscopy, Far Western blot, and pulldown experiments a physical interaction of Vpr with the major host PPIase cyclophilin A (CypA) is now demonstrated [22].
• Taken together, our results demonstrate that CyPB-binding sites are mainly associated with resting cells of the helper T lymphocyte, and that CyPB might modulate the distribution of CsA through the drug targeting to sensitive cells [23].
• The polymerase chain reaction (PCR) technique was used to generate a unique probe complementary to the hydrophobic 5' end of the human cyclophilin B gene [24].
• By site-directed mutagenesis of CyPD that compromises peptidyl-prolyl cis-trans isomerase (PPIase) activity, we demonstrate that the mechanism involved in this protective effect requires PPIase activity [25].
• Cyclophilin B (CypB) is a potential biomarker for pancreatic cancer. An RNA aptamer (M9-5) was selected by comparing human pancreatic cell secretomes by in vitro aptamer selection technique (SELEX). The aptamer (M9-5) discriminates between the sera of pancreatic cancer patients and healthy volunteers with high sensitivity and specificity. Utilizing chromatographic methods and mass-spectrometric analysis the M9-5 target was identified as CypB. Additionally, by using ELISA it was demonstrated that the CypB level is elevated in the sera of pancreatic cancer patients as compared to the healthy volunteers [26]. Recent work has demonstrated that the M9-5 could discriminate between recombinant human Cyclophilin B expressed in mammalian cells versus bacteria. Using mass-spectrometric analysis, post-translational modifications on Cyclophilin B were discovered that might be responsible for this aptamer selectivity [27].

References