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Gene Review

PPIA  -  peptidylprolyl isomerase A (cyclophilin A)

Homo sapiens

Synonyms: CYPA, CYPH, Cyclophilin A, Cyclosporin A-binding protein, HEL-S-69p, ...
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Disease relevance of PPIA


Psychiatry related information on PPIA


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


Biological context of PPIA


Anatomical context of PPIA


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


Regulatory relationships of PPIA


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


  1. Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells. Braaten, D., Luban, J. EMBO J. (2001) [Pubmed]
  2. Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Price, E.R., Zydowsky, L.D., Jin, M.J., Baker, C.H., McKeon, F.D., Walsh, C.T. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  3. Cyclophilin binding to the human immunodeficiency virus type 1 Gag polyprotein is mimicked by an anti-cyclosporine antibody. Franke, E.K., Chen, B.X., Tatsis, I., Diamanduros, A., Erlanger, B.F., Luban, J. J. Virol. (1995) [Pubmed]
  4. A Mutation in Alpha Helix 3 of CA Renders Human Immunodeficiency Virus Type 1 Cyclosporin A Resistant and Dependent: Rescue by a Second-Site Substitution in a Distal Region of CA. Yang, R., Aiken, C. J. Virol. (2007) [Pubmed]
  5. Cellular functions of immunophilins. Marks, A.R. Physiol. Rev. (1996) [Pubmed]
  6. Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid. Gamble, T.R., Vajdos, F.F., Yoo, S., Worthylake, D.K., Houseweart, M., Sundquist, W.I., Hill, C.P. Cell (1996) [Pubmed]
  7. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Towers, G.J., Hatziioannou, T., Cowan, S., Goff, S.P., Luban, J., Bieniasz, P.D. Nat. Med. (2003) [Pubmed]
  8. Specific incorporation of cyclophilin A into HIV-1 virions. Franke, E.K., Yuan, H.E., Luban, J. Nature (1994) [Pubmed]
  9. Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human TRIM5{alpha} Antiviral Activity. Keckesova, Z., Ylinen, L.M., Towers, G.J. J. Virol. (2006) [Pubmed]
  10. Functional association of cyclophilin A with HIV-1 virions. Thali, M., Bukovsky, A., Kondo, E., Rosenwirth, B., Walsh, C.T., Sodroski, J., Göttlinger, H.G. Nature (1994) [Pubmed]
  11. Structure of human cyclophilin A in complex with the novel immunosuppressant sanglifehrin A at 1.6 A resolution. Kallen, J., Sedrani, R., Zenke, G., Wagner, J. J. Biol. Chem. (2005) [Pubmed]
  12. Evidence that intracellular cyclophilin A and cyclophilin A/CD147 receptor-mediated ERK1/2 signalling can protect neurons against in vitro oxidative and ischemic injury. Boulos, S., Meloni, B.P., Arthur, P.G., Majda, B., Bojarski, C., Knuckey, N.W. Neurobiol. Dis. (2007) [Pubmed]
  13. Assignment of cyclophilin A (PPIA) to human chromosome band 7p13by in situ hybridization. Braaten, D., Wellington, S., Warburton, D., Luban, J. Cytogenet. Cell Genet. (1996) [Pubmed]
  14. Active site residues of cyclophilin A are crucial for its signaling activity via CD147. Yurchenko, V., Zybarth, G., O'Connor, M., Dai, W.W., Franchin, G., Hao, T., Guo, H., Hung, H.C., Toole, B., Gallay, P., Sherry, B., Bukrinsky, M. J. Biol. Chem. (2002) [Pubmed]
  15. AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Candé, C., Vahsen, N., Kouranti, I., Schmitt, E., Daugas, E., Spahr, C., Luban, J., Kroemer, R.T., Giordanetto, F., Garrido, C., Penninger, J.M., Kroemer, G. Oncogene (2004) [Pubmed]
  16. Cyclophilin A-independent replication of a human immunodeficiency virus type 1 isolate carrying a small portion of the simian immunodeficiency virus SIV(MAC) gag capsid region. Fujita, M., Yoshida, A., Miyaura, M., Sakurai, A., Akari, H., Koyama, A.H., Adachi, A. J. Virol. (2001) [Pubmed]
  17. Effects of cyclophilin A on cell proliferation and gene expressions in human vascular smooth muscle cells and endothelial cells. Yang, H., Li, M., Chai, H., Yan, S., Lin, P., Lumsden, A.B., Yao, Q., Chen, C. J. Surg. Res. (2005) [Pubmed]
  18. A novel and functional interaction between cyclophilin A and prolactin receptor. Syed, F., Rycyzyn, M.A., Westgate, L., Clevenger, C.V. Endocrine (2003) [Pubmed]
  19. Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147. Li, M., Zhai, Q., Bharadwaj, U., Wang, H., Li, F., Fisher, W.E., Chen, C., Yao, Q. Cancer (2006) [Pubmed]
  20. One novel quinoxaline derivative as a potent human cyclophilin A inhibitor shows highly inhibitory activity against mouse spleen cell proliferation. Li, J., Chen, J., Zhang, L., Wang, F., Gui, C., Zhang, L., Qin, Y., Xu, Q., Liu, H., Nan, F., Shen, J., Bai, D., Chen, K., Shen, X., Jiang, H. Bioorg. Med. Chem. (2006) [Pubmed]
  21. X-ray structure of a cyclophilin B/cyclosporin complex: comparison with cyclophilin A and delineation of its calcineurin-binding domain. Mikol, V., Kallen, J., Walkinshaw, M.D. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  22. Regulation of CD147 cell surface expression: involvement of the proline residue in the CD147 transmembrane domain. Yurchenko, V., Pushkarsky, T., Li, J.H., Dai, W.W., Sherry, B., Bukrinsky, M. J. Biol. Chem. (2005) [Pubmed]
  23. Vif counteracts a cyclophilin A-imposed inhibition of simian immunodeficiency viruses in human cells. Takeuchi, H., Buckler-White, A., Goila-Gaur, R., Miyagi, E., Khan, M.A., Opi, S., Kao, S., Sokolskaja, E., Pertel, T., Luban, J., Strebel, K. J. Virol. (2007) [Pubmed]
  24. Cyclophilin, TRIM5, and innate immunity to HIV-1. Sokolskaja, E., Luban, J. Curr. Opin. Microbiol. (2006) [Pubmed]
  25. Cyclophilin A: an auxiliary but not necessary cofactor for TRIM5alpha restriction of HIV-1. Stremlau, M., Song, B., Javanbakht, H., Perron, M., Sodroski, J. Virology (2006) [Pubmed]
  26. Nucleocapsid protein of SARS coronavirus tightly binds to human cyclophilin A. Luo, C., Luo, H., Zheng, S., Gui, C., Yue, L., Yu, C., Sun, T., He, P., Chen, J., Shen, J., Luo, X., Li, Y., Liu, H., Bai, D., Shen, J., Yang, Y., Li, F., Zuo, J., Hilgenfeld, R., Pei, G., Chen, K., Shen, X., Jiang, H. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  27. Peptidylprolyl isomerase A (PPIA) as a preferred internal control over GAPDH and beta-actin in quantitative RNA analyses. Feroze-Merzoug, F., Berquin, I.M., Dey, J., Chen, Y.Q. BioTechniques (2002) [Pubmed]
  28. Possible involvement of calcineurin in retinoic acid-induced inhibition of leukemic HL-60 cell proliferation. Kihira, H., Hiasa, A., Yamamoto, M., Katayama, N., Kuno, T., Ohtsuka, K., Shiku, H., Nishikawa, M. Int. J. Oncol. (1998) [Pubmed]
  29. Cyclophilin A is required for CXCR4-mediated nuclear export of heterogeneous nuclear ribonucleoprotein A2, activation and nuclear translocation of ERK1/2, and chemotactic cell migration. Pan, H., Luo, C., Li, R., Qiao, A., Zhang, L., Mines, M., Nyanda, A.M., Zhang, J., Fan, G.H. J. Biol. Chem. (2008) [Pubmed]
  30. Phosphorylation-dependent interaction of the asialoglycoprotein receptor with molecular chaperones. Huang, T., Deng, H., Wolkoff, A.W., Stockert, R.J. J. Biol. Chem. (2002) [Pubmed]
  31. Trim-cyclophilin A fusion proteins can restrict human immunodeficiency virus type 1 infection at two distinct phases in the viral life cycle. Yap, M.W., Dodding, M.P., Stoye, J.P. J. Virol. (2006) [Pubmed]
  32. Use of a combined ex vivo/in vivo population approach for screening of human genes involved in the human immunodeficiency virus type 1 life cycle for variants influencing disease progression. Bleiber, G., May, M., Martinez, R., Meylan, P., Ott, J., Beckmann, J.S., Telenti, A. J. Virol. (2005) [Pubmed]
  33. 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. Misumi, S., Fuchigami, T., Takamune, N., Takahashi, I., Takama, M., Shoji, S. J. Virol. (2002) [Pubmed]
  34. Cyclophilin A interacts with HIV-1 Vpr and is required for its functional expression. Zander, K., Sherman, M.P., Tessmer, U., Bruns, K., Wray, V., Prechtel, A.T., Schubert, E., Henklein, P., Luban, J., Neidleman, J., Greene, W.C., Schubert, U. J. Biol. Chem. (2003) [Pubmed]
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