Disease relevance of PPIA

• HIV-1 replication in PPIA(-/-) cells was decreased and not inhibited further by cyclosporin or gag mutations that disrupt Gag's interaction with cyclophilins, indicating that no other cyclophilin family members promote HIV-1 replication [1].
• Finally, virions from PPIA(-/-) cells possessed no obvious biochemical abnormalities but were less infectious than virions from wild-type cells [1].
• The defective replication phenotype was specific for wild-type HIV-1 since HIV-2/SIV isolates, as well as HIV-1 bearing a gag mutation that confers cyclosporin resistance, replicated the same in PPIA(+/+) and PPIA(-/-) cells [1].
• This family is distinguished from the cyclophilin A (CyPA) family by the presence of endoplasmic reticulum (ER)-directed signal sequences. hCyPB has a hydrophobic leader sequence not found in hCyPA, and its first 25 amino acids are removed upon expression in Escherichia coli [2].
• B11 1.4 does not recognize the capsids of other retroviruses, and binding is inhibited by cyclosporine or by cyclophilin A [3].

Psychiatry related information on PPIA

• RNA interference-mediated reduction of CypA expression enhanced the permissiveness of HeLa cells to infection by the T54A mutant [4].

High impact information on PPIA

• The prototypic members of the immunophilin family, cyclophilin A and FKPB12, were discovered on the basis of their ability to bind and mediate the immunosuppressive effects of the drugs cyclosporin, FK506, and rapamycin [5].
• We report the 2.36 A crystal structure of the N-terminal domain of HIV-1 capsid (residues 1-151) in complex with human cyclophilin A. A single exposed capsid loop (residues 85-93) binds in the enzyme's active site, and Pro-90 adopts an unprecedented trans conformation [6].
• The structure suggests how cyclophilin A can act as a sequence-specific binding protein and a nonspecific prolyl isomerase [6].
• In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding [7].
• Disruption of a single proline blocks the Gag-cyclophilin interaction in vitro, prevents cyclophilin A incorporation into virions, and inhibits HIV-1 replication [8].

Chemical compound and disease context of PPIA

• Cyclophilin A is recruited into nascent human immunodeficiency virus type 1 (HIV-1) virions as well as incoming HIV-1 capsids, where it isomerizes an exposed proline residue [9].
• Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human TRIM5{alpha} Antiviral Activity [9].
• Moreover, SDZ NIM811 inhibited the replication of HIV-1 but was inactive against SIVMAC, a primate immunodeficiency virus closely related to HIV-1, which does not incorporate cyclophilin A [10].
• Sanglifehrin A (SFA) is a novel immunosuppressant isolated from Streptomyces sp. that binds strongly to the human immunophilin cyclophilin A (CypA) [11].
• In the present study, we have demonstrated that adenoviral-mediated over-expression of cyclophilin A in rat cortical neuronal cultures can protect neurons from oxidative stress (induced by cumene hydroperoxide) and in vitro ischemia (induced by oxygen glucose deprivation) [12].

Biological context of PPIA

• Assignment of cyclophilin A (PPIA) to human chromosome band 7p13by in situ hybridization [13].
• Active site residues of cyclophilin A are crucial for its signaling activity via CD147 [14].
• The mechanisms underlying CyPA-mediated signaling and chemotaxis are unknown [14].
• During the initial, caspase-independent stage of chromatin condensation that accompanies apoptosis, AIF and CypA were found to coimmunolocalize in the nucleus [15].
• Recombinant AIF and CypA proteins synergized in vitro in the degradation of plasmid DNA, as well as in the capacity to induce DNA loss in purified nuclei [15].

Anatomical context of PPIA

• Although expressed predominantly as an intracellular molecule, CyPA is secreted by cells in response to inflammatory stimuli and is a potent neutrophil and eosinophil chemoattractant in vitro and in vivo [14].
• Although this chimeric virus was unable to grow in monkey lymphocytic cells like wild-type (wt) HIV-1 did, it grew much better than wt virus in the presence of cyclosporin A in a human cell line which supports HIV-1 replication in a CyPA-dependent manner [16].
• Effects of cyclophilin A on cell proliferation and gene expressions in human vascular smooth muscle cells and endothelial cells [17].
• CypA was co-immunoprecipitated with the PRLR in vivo from the breast epithelial cell line T47D and Chinese hamster ovary transfectants overexpressing transfected human PRLR [18].
• RESULTS: Pancreatic cancer cell lines expressed significantly higher levels of CypA and CD147 than normal human pancreatic ductal epithelium (HPDE) cells [19].

Associations of PPIA with chemical compounds

• Cyclophilin A (CyPA), a ubiquitously distributed intracellular protein, is a peptidylprolyl cis-trans-isomerase and the major target of the potent immunosuppressive drug cyclosporin A [14].
• In addition, in vitro binding assays demonstrated a direct interaction of CypA with the PRLR, in the presence or absence of cyclosporine [18].
• One novel quinoxaline derivative as a potent human cyclophilin A inhibitor shows highly inhibitory activity against mouse spleen cell proliferation [20].
• 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 [21].
• Peptide binding studies demonstrated specific interaction between CypA and the proline-containing peptide from the CD147 transmembrane domain [22].
• Infection of CypA knockout Jurkat cells or treatment of Jurkat cells with cyclosporine A eliminated the Vif-sensitive inhibition and resulted in replication profiles that were similar for wild-type and vif-deficient SIVagm [23].

Physical interactions of PPIA

• Solution binding experiments demonstrated that the transmembrane domain was both necessary and sufficient for CD147 binding to cyclophilin A (CypA) [22].
• The peptidyl-prolyl isomerase cyclophilin A (CypA) binds a proline-rich loop on the surface of HIV-1 capsid (CA) [24].
• Disruption of Cyp A binding to CA partially relieved the block to HIV-1 infection imposed by several TRIM5alpha variants, but Cyp A-CA binding was not absolutely required for TRIM5alpha antiviral activity [25].
• Nucleocapsid protein of SARS coronavirus tightly binds to human cyclophilin A [26].

Regulatory relationships of PPIA

• Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147 [19].
• Peptidylprolyl isomerase A (PPIA) as a preferred internal control over GAPDH and beta-actin in quantitative RNA analyses [27].
• These proximal actions had profound downstream effects: CypA overexpression significantly enhanced the basal and PRL-stimulated expression from a beta-casein reporter construct [18].
• The FKBP12 expression increased during ATRA-induced differentiation and expression of cyclophilin A remained unchanged [28].
• CXCL12-induced chemotaxis of HEK293 cells stably expressing CXCR4 or Jurkat T cells was inhibited by CyPA RNAi or CsA treatment [29].

Other interactions of PPIA

• Mass spectrometer and immunoblot analysis identified five of these proteins as gp96, HSP70, HSP90, cyclophilin-A, and FKBP18 [30].
• AIF mutants lacking the CypA-binding domain were inefficient apoptosis sensitizers in transfection experiments [15].
• In owl monkeys, the B30.2 domain of Trim5 has been replaced by cyclophilin A (CypA) following a retrotransposition [31].
• The critical interaction between CA and Trim-CypA appears to take place soon after viral entry [31].
• This led to the proposition of three alleles of PML, TSG101, and PPIA as potentially associated with differences in progression of HIV-1 disease [32].

Analytical, diagnostic and therapeutic context of PPIA

• Three isoforms of cyclophilin A associated with human immunodeficiency virus type 1 were found by proteomics by using two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry [33].
• METHODS: The expression of CypA and CD147 in human pancreatic cancer cell lines and tissues was determined with real-time reverse transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunostaining [19].
• Co-immunoprecipitation studies also showed an association of CypA with Jak2 [18].
• By using the surface plasmon resonance (SPR) and fluorescence titration techniques, the kinetic analysis of CypA/DC838 interaction was quantitatively performed [20].
• 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 [34].

References