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Gene Review

PPID  -  peptidylprolyl isomerase D

Homo sapiens

Synonyms: 40 kDa peptidyl-prolyl cis-trans isomerase, CYP-40, CYP40, CYPD, Cyclophilin-40, ...
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Disease relevance of PPID

  • Although PPID is recognized to be a different form of pituitary-dependent hyperadrenocorticism than is seen in canine or human patients, relatively little is known about the pathophysiology and natural progression of the disease [1].
  • The time point at which medication should be added to improved health care and management changes is not currently known, but loss of body condition and development of hyperglycemia suggest more advanced PPID that would likely benefit from drug therapy [1].
  • Application of heat stress elicited a marked redistribution of CyP40 protein in MCF-7 cells from a predominantly nucleolar localization, with some nuclear and cytoplasmic staining, to a pattern characterized by a pronounced nuclear accumulation of CyP40, with no distinguishable nucleolar staining [2].
  • FK506 and FK506-derived inhibitors of the FK506-binding protein (FKBP)-type peptidylprolyl cis/trans-isomerases (PPIase) display potent neuroprotective and neuroregenerative properties in various neurodegeneration models, showing the importance of neuroimmunophilins as targets for the treatment of acute and chronic neurodegenerative diseases [3].
  • The Escherichia coli periplasmic chaperone and peptidyl-prolyl isomerase (PPIase) SurA facilitates the maturation of outer membrane porins [4].

High impact information on PPID

  • This conformation of CsA is similar to that recently observed in the complex with the rotamase cyclophilin, its binding protein in vivo, and totally different from its conformation in an isolated form as determined from x-ray and nuclear magnetic resonance analysis [5].
  • To understand the molecular mechanism of PTPA activity, Ypa1 was cocrystallized with a proline-containing PPIase peptide substrate [6].
  • The most common type of cyclophilins are the 18 kDa cytosolic proteins containing only the highly conserved core domain for PPIase and CsA binding activities [7].
  • A cyclophilin-related protein involved in the function of natural killer cells [8].
  • Interestingly, we found that the PPIase-dependent apoptosis suppression by cyclophilin D correlated with the amounts of mitochondrial-bound hexokinase II, which has anti-apoptotic activity [9].

Chemical compound and disease context of PPID


Biological context of PPID


Anatomical context of PPID

  • We also found that two different changes in the N-terminal extension that abated binding to GAGs prevented adhesion of peripheral blood T-lymphocytes to coated CyPB, whereas abbrogation of the PPIase activity had no effect [14].
  • TLP20 is suggested to be the major PPIase and protein folding catalyst in the thylakoid lumen of plant chloroplasts [15].
  • The Ran-binding protein 2 (RanBP2) is a large scaffold cyclophilin-related protein expressed in photoreceptor cells [16].
  • Ng-MIP, a surface-exposed lipoprotein of Neisseria gonorrhoeae, has a peptidyl-prolyl cis/trans isomerase (PPIase) activity and is involved in persistence in macrophages [17].
  • All but one of the PPIase inhibiting mAbs were able to significantly inhibit the early establishment and initiation of an intracellular infection of the bacteria in Acanthamoeba castellanii, the natural host, and in the human phagocytic cell line U937 [18].

Associations of PPID with chemical compounds


Regulatory relationships of PPID

  • We proposed that TRH directly stimulates the PI in normal and PPID-affected horses to release proopiomelanocortin (POMC) derived peptides [21].

Other interactions of PPID

  • Hop, which contains multiple units of the TPR motif, was shown to be a direct competitor with CyP40 for Hsc70 binding [22].
  • However, the affinities of the PPIases are different with FKBP52 exhibiting the strongest interaction and Cyp40 the weakest [23].
  • Interestingly, Cyp40 and FKBP51 are the more potent chaperones [23].
  • To determine the sequence of this protein, degenerate oligonucleotide primers based on bovine brain CyP-40 tryptic peptides were used to generate a polymerase chain reaction fragment of CyP-40 cDNA [11].
  • The presence of TRH receptor mRNA in PI tissue from both normal and PPID horses was confirmed using reverse transcriptase polymerase chain reaction [21].

Analytical, diagnostic and therapeutic context of PPID

  • Using a carboxyl-terminal CyP40 construct as template, 24 amino acids from the TPR and flanking acidic and basic domains were individually mutated by site-directed mutagenesis, and the mutants were coexpressed in yeast with a carboxyl-terminal Hsp90beta construct and qualitatively assessed for binding using a beta-galactosidase filter assay [24].
  • Assessments of efficacy included measures of the sum of pain intensity differences (SPID), total pain relief (TOPAR) and peak analgesia (PPID) [25].
  • Sequence analysis of wis2+ reveals that it encodes a 40 kDa cyclophilin-like protein, homologous to the mammalian cyclophilin 40 [7].
  • METHODS: Allelic loss at CyP40 was determined from patients' matched tumor and normal breast tissue using Genescan 672 software analysis of fluorescently labeled, PAGE-separated PCR products incorporating the marker [26].


  1. Pituitary pars intermedia dysfunction: equine Cushing's disease. Schott, H.C. Vet. Clin. North Am. Equine Pract. (2002) [Pubmed]
  2. Human cyclophilin 40 is a heat shock protein that exhibits altered intracellular localization following heat shock. Mark, P.J., Ward, B.K., Kumar, P., Lahooti, H., Minchin, R.F., Ratajczak, T. Cell Stress Chaperones (2001) [Pubmed]
  3. The specific FKBP38 inhibitor N-(N',N'-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. Edlich, F., Weiwad, M., Wildemann, D., Jarczowski, F., Kilka, S., Moutty, M.C., Jahreis, G., Lücke, C., Schmidt, W., Striggow, F., Fischer, G. J. Biol. Chem. (2006) [Pubmed]
  4. The periplasmic chaperone SurA exploits two features characteristic of integral outer membrane proteins for selective substrate recognition. Hennecke, G., Nolte, J., Volkmer-Engert, R., Schneider-Mergener, J., Behrens, S. J. Biol. Chem. (2005) [Pubmed]
  5. A conformation of cyclosporin A in aqueous environment revealed by the X-ray structure of a cyclosporin-Fab complex. Altschuh, D., Vix, O., Rees, B., Thierry, J.C. Science (1992) [Pubmed]
  6. Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity. Leulliot, N., Vicentini, G., Jordens, J., Quevillon-Cheruel, S., Schiltz, M., Barford, D., van Tilbeurgh, H., Goris, J. Mol. Cell (2006) [Pubmed]
  7. A multicopy suppressor of a cell cycle defect in S. pombe encodes a heat shock-inducible 40 kDa cyclophilin-like protein. Weisman, R., Creanor, J., Fantes, P. EMBO J. (1996) [Pubmed]
  8. A cyclophilin-related protein involved in the function of natural killer cells. Anderson, S.K., Gallinger, S., Roder, J., Frey, J., Young, H.A., Ortaldo, J.R. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  9. Suppression of apoptosis by cyclophilin D via stabilization of hexokinase II mitochondrial binding in cancer cells. Machida, K., Ohta, Y., Osada, H. J. Biol. Chem. (2006) [Pubmed]
  10. Estradiol-regulated expression of the immunophilins cyclophilin 40 and FKBP52 in MCF-7 breast cancer cells. Kumar, P., Mark, P.J., Ward, B.K., Minchin, R.F., Ratajczak, T. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  11. Cyclophilin-40, a protein with homology to the P59 component of the steroid receptor complex. Cloning of the cDNA and further characterization. Kieffer, L.J., Seng, T.W., Li, W., Osterman, D.G., Handschumacher, R.E., Bayney, R.M. J. Biol. Chem. (1993) [Pubmed]
  12. Cyclophilin-40: evidence for a dimeric complex with hsp90. Hoffmann, K., Handschumacher, R.E. Biochem. J. (1995) [Pubmed]
  13. Regulation of the Hsp90-binding immunophilin, cyclophilin 40, is mediated by multiple sites for GA-binding protein (GABP). Kumar, P., Ward, B.K., Minchin, R.F., Ratajczak, T. Cell Stress Chaperones (2001) [Pubmed]
  14. 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. Carpentier, M., Allain, F., Slomianny, M.C., Durieux, S., Vanpouille, C., Haendler, B., Spik, G. Biochemistry (2002) [Pubmed]
  15. The major peptidyl-prolyl isomerase activity in thylakoid lumen of plant chloroplasts belongs to a novel cyclophilin TLP20. Edvardsson, A., Eshaghi, S., Vener, A.V., Andersson, B. FEBS Lett. (2003) [Pubmed]
  16. The zinc finger cluster domain of RanBP2 is a specific docking site for the nuclear export factor, exportin-1. Singh, B.B., Patel, H.H., Roepman, R., Schick, D., Ferreira, P.A. J. Biol. Chem. (1999) [Pubmed]
  17. Ng-MIP, a surface-exposed lipoprotein of Neisseria gonorrhoeae, has a peptidyl-prolyl cis/trans isomerase (PPIase) activity and is involved in persistence in macrophages. Leuzzi, R., Serino, L., Scarselli, M., Savino, S., Fontana, M.R., Monaci, E., Taddei, A., Fischer, G., Rappuoli, R., Pizza, M. Mol. Microbiol. (2005) [Pubmed]
  18. The PPIase active site of Legionella pneumophila Mip protein is involved in the infection of eukaryotic host cells. Helbig, J.H., König, B., Knospe, H., Bubert, B., Yu, C., Lück, C.P., Riboldi-Tunnicliffe, A., Hilgenfeld, R., Jacobs, E., Hacker, J., Fischer, G. Biol. Chem. (2003) [Pubmed]
  19. Characterization of cyclophilin 40: highly conserved protein that directly associates with Hsp90. Yokoi, H., Kondo, H., Furuya, A., Hanai, N., Ikeda, J.E., Anazawa, H. Biol. Pharm. Bull. (1996) [Pubmed]
  20. Expression of human cyclophilin-40 and the effect of the His141-->Trp mutation on catalysis and cyclosporin A binding. Hoffmann, K., Kakalis, L.T., Anderson, K.S., Armitage, I.M., Handschumacher, R.E. Eur. J. Biochem. (1995) [Pubmed]
  21. Alpha-melanocyte stimulating hormone release in response to thyrotropin releasing hormone in healthy horses, horses with pituitary pars intermedia dysfunction and equine pars intermedia explants. McFarlane, D., Beech, J., Cribb, A. Domest. Anim. Endocrinol. (2006) [Pubmed]
  22. Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70. Carrello, A., Allan, R.K., Morgan, S.L., Owen, B.A., Mok, D., Ward, B.K., Minchin, R.F., Toft, D.O., Ratajczak, T. Cell Stress Chaperones (2004) [Pubmed]
  23. Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40. Pirkl, F., Buchner, J. J. Mol. Biol. (2001) [Pubmed]
  24. A structure-based mutational analysis of cyclophilin 40 identifies key residues in the core tetratricopeptide repeat domain that mediate binding to Hsp90. Ward, B.K., Allan, R.K., Mok, D., Temple, S.E., Taylor, P., Dornan, J., Mark, P.J., Shaw, D.J., Kumar, P., Walkinshaw, M.D., Ratajczak, T. J. Biol. Chem. (2002) [Pubmed]
  25. Clinical experience with flupirtine in the U.S. McMahon, F.G., Arndt, W.F., Newton, J.J., Montgomery, P.A., Perhach, J.L. Postgraduate medical journal. (1987) [Pubmed]
  26. Allelic loss of cyclophilin 40, an estrogen receptor-associated immunophilin, in breast carcinomas. Ward, B.K., Kumar, P., Turbett, G.R., Edmondston, J.E., Papadimitriou, J.M., Laing, N.G., Ingram, D.M., Minchin, R.F., Ratajczak, T. J. Cancer Res. Clin. Oncol. (2001) [Pubmed]
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