PPIC explained

Peptidyl-prolyl cis-trans isomerase C (PPIC) is an enzyme that in humans is encoded by the PPIC gene on chromosome 5. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins.^{[1] [2] [3]} In addition, PPIC participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer.^{[4] [5] [6] [7]}

Structure

Like other cyclophilins, PPIC forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel.^[6] PPIC in particular is composed of 212 residues and contains a hydrophobic, ER-targeting sequence at the N-terminal. The PPIase domain is homologous to PPIA and can be bound and inhibited by CsA.^[2]

Function

The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins.^[3] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.^{[4] [8]} The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn).^{[4] [6]} As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within the cell or secreted by the cell.^[5] In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types, though PPIC especially is highly expressed in kidney.^{[5] [6] [9]} In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation.^{[4] [5] [6]} Along with PPIB, PPIC localizes to the endoplasmic reticulum (ER), where it maintains redox homeostasis. Depletion of these two cyclophilins lead to hyperoxidation of the ER.^[7] In the brain, PPIC complexes with cyclophilin C-associated protein (CyCAP) to activate microglia and macrophage function via the calcineurin/NFAT pathway.^[9]

Clinical Significance

As a cyclophilin, PPIC binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation.^[5]

In cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury.^[5] Similarly, PPIC may confer neuroprotection by forming a complex with CyCAP to activate survival mechanisms and mitigate ischemic damage in the brain.^[9]

Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated.^[5] For instance, studies identify PPIC as a reliable indicator of circulating tumor cells in epithelial ovarian cancer (EOC) and, thus, may serve as a biomarker for detection and treatment of the cancer.^[10]

Interactions

PPIC has been shown to interact with:

• CsA,^{[9] [11]}
• CyCAP,^{[9] [11]}
• calcineurin,^[9] and
• NFATc1.^[9]

Further reading

• Friedman J, Weissman I . Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA . Cell . 66 . 4 . 799–806 . Aug 1991 . 1652374 . 10.1016/0092-8674(91)90123-G . 205020327 . free .
• Price ER, Jin M, Lim D, Pati S, Walsh CT, McKeon FD . Cyclophilin B trafficking through the secretory pathway is altered by binding of cyclosporin A . Proceedings of the National Academy of Sciences of the United States of America . 91 . 9 . 3931–5 . Apr 1994 . 7909608 . 43696 . 10.1073/pnas.91.9.3931 . 1994PNAS...91.3931P . free .
• Friedman J, Trahey M, Weissman I . Cloning and characterization of cyclophilin C-associated protein: a candidate natural cellular ligand for cyclophilin C . Proceedings of the National Academy of Sciences of the United States of America . 90 . 14 . 6815–9 . Jul 1993 . 8341703 . 47023 . 10.1073/pnas.90.14.6815 . 1993PNAS...90.6815F . free .
• Montague JW, Hughes FM, Cidlowski JA . Native recombinant cyclophilins A, B, and C degrade DNA independently of peptidylprolyl cis-trans-isomerase activity. Potential roles of cyclophilins in apoptosis . The Journal of Biological Chemistry . 272 . 10 . 6677–84 . Mar 1997 . 9045699 . 10.1074/jbc.272.10.6677 . free .
• Trahey M, Weissman IL . Cyclophilin C-associated protein: a normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo . Proceedings of the National Academy of Sciences of the United States of America . 96 . 6 . 3006–11 . Mar 1999 . 10077627 . 15885 . 10.1073/pnas.96.6.3006 . 1999PNAS...96.3006T . free .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• Davis TL, Walker JR, Campagna-Slater V, etal . Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases . PLOS Biol. . 8 . 7 . e1000439 . 2010 . 20676357 . 10.1371/journal.pbio.1000439 . 2911226 . free .

Notes and References

1. Sugano S, Kim DW, Yu YS, Mizushima-Sugano J, Yoshitomo K, Watanabe S, Suzuki F, Yamaguchi N . Use of an epitope-tagged cDNA library to isolate cDNAs encoding proteins with nuclear localization potential . Gene . 120 . 2 . 227–33 . Oct 1992 . 1383094 . 10.1016/0378-1119(92)90097-9 .
2. Schneider H, Charara N, Schmitz R, Wehrli S, Mikol V, Zurini MG, Quesniaux VF, Movva NR . Human cyclophilin C: primary structure, tissue distribution, and determination of binding specificity for cyclosporins . Biochemistry . 33 . 27 . 8218–24 . Jul 1994 . 8031755 . 10.1021/bi00193a007 .
3. Web site: Entrez Gene: PPIC peptidylprolyl isomerase C (cyclophilin C).
4. Kazui T, Inoue N, Yamada O, Komatsu S . Selective cerebral perfusion during operation for aneurysms of the aortic arch: a reassessment . The Annals of Thoracic Surgery . 53 . 1 . 109–14 . Jan 1992 . 1530810 . 10.1016/0003-4975(92)90767-x. free .
5. Yao Q, Li M, Yang H, Chai H, Fisher W, Chen C . Roles of cyclophilins in cancers and other organ systems . World Journal of Surgery . 29 . 3 . 276–80 . Mar 2005 . 15706440 . 10.1007/s00268-004-7812-7 . 11678319 .
6. Wang T, Yun CH, Gu SY, Chang WR, Liang DC . 1.88 A crystal structure of the C domain of hCyP33: a novel domain of peptidyl-prolyl cis-trans isomerase . Biochemical and Biophysical Research Communications . 333 . 3 . 845–9 . Aug 2005 . 15963461 . 10.1016/j.bbrc.2005.06.006 .
7. Stocki P, Chapman DC, Beach LA, Williams DB . Depletion of cyclophilins B and C leads to dysregulation of endoplasmic reticulum redox homeostasis . The Journal of Biological Chemistry . 289 . 33 . 23086–96 . Aug 2014 . 24990953 . 10.1074/jbc.M114.570911 . 4132807. free .
8. Hoffmann H, Schiene-Fischer C . Functional aspects of extracellular cyclophilins . Biological Chemistry . 395 . 7–8 . 721–35 . Jul 2014 . 24713575 . 10.1515/hsz-2014-0125 . 32395688 .
9. Yamaguchi R, Hosaka M, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T . Cyclophilin C-associated protein regulation of phagocytic functions via NFAT activation in macrophages . Brain Research . 1397 . 55–65 . Jun 2011 . 21435337 . 10.1016/j.brainres.2011.03.036 . 28737748 .
10. Obermayr E, Castillo-Tong DC, Pils D, Speiser P, Braicu I, Van Gorp T, Mahner S, Sehouli J, Vergote I, Zeillinger R . Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance -- a study of the OVCAD consortium . Gynecologic Oncology . 128 . 1 . 15–21 . Jan 2013 . 23017820 . 10.1016/j.ygyno.2012.09.021 .
11. Trahey M, Weissman IL . Cyclophilin C-associated protein: a normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo . Proceedings of the National Academy of Sciences of the United States of America . 96 . 6 . 3006–11 . Mar 1999 . 10077627 . 10.1073/pnas.96.6.3006 . 15885. 1999PNAS...96.3006T . free .