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词条 PPIC
释义

  1. Structure

  2. Function

  3. Clinical Significance

  4. Interactions

  5. References

  6. Further reading

{{For|the institution with the same acronym|Public Policy Institute of California}}{{Infobox_gene}}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 in 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]
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References

1. ^{{cite journal | vauthors = Sugano S, Kim DW, Yu YS, Mizushima-Sugano J, Yoshitomo K, Watanabe S, Suzuki F, Yamaguchi N | title = Use of an epitope-tagged cDNA library to isolate cDNAs encoding proteins with nuclear localization potential | journal = Gene | volume = 120 | issue = 2 | pages = 227–33 | date = Oct 1992 | pmid = 1383094 | pmc = | doi = 10.1016/0378-1119(92)90097-9 }}
2. ^1 {{cite journal | vauthors = Schneider H, Charara N, Schmitz R, Wehrli S, Mikol V, Zurini MG, Quesniaux VF, Movva NR | title = Human cyclophilin C: primary structure, tissue distribution, and determination of binding specificity for cyclosporins | journal = Biochemistry | volume = 33 | issue = 27 | pages = 8218–24 | date = Jul 1994 | pmid = 8031755 | pmc = | doi = 10.1021/bi00193a007 }}
3. ^1 {{cite web | title = Entrez Gene: PPIC peptidylprolyl isomerase C (cyclophilin C)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5480| accessdate = }}
4. ^1 2 3 {{cite journal | vauthors = Kazui T, Inoue N, Yamada O, Komatsu S | title = Selective cerebral perfusion during operation for aneurysms of the aortic arch: a reassessment | journal = The Annals of Thoracic Surgery | volume = 53 | issue = 1 | pages = 109–14 | date = Jan 1992 | pmid = 1530810 | doi=10.1016/0003-4975(92)90767-x}}
5. ^1 2 3 4 5 6 {{cite journal | vauthors = Yao Q, Li M, Yang H, Chai H, Fisher W, Chen C | title = Roles of cyclophilins in cancers and other organ systems | journal = World Journal of Surgery | volume = 29 | issue = 3 | pages = 276–80 | date = Mar 2005 | pmid = 15706440 | doi = 10.1007/s00268-004-7812-7 }}
6. ^1 2 3 4 {{cite journal | vauthors = Wang T, Yun CH, Gu SY, Chang WR, Liang DC | title = 1.88 A crystal structure of the C domain of hCyP33: a novel domain of peptidyl-prolyl cis-trans isomerase | journal = Biochemical and Biophysical Research Communications | volume = 333 | issue = 3 | pages = 845–9 | date = Aug 2005 | pmid = 15963461 | doi = 10.1016/j.bbrc.2005.06.006 }}
7. ^1 {{cite journal | vauthors = Stocki P, Chapman DC, Beach LA, Williams DB | title = Depletion of cyclophilins B and C leads to dysregulation of endoplasmic reticulum redox homeostasis | journal = The Journal of Biological Chemistry | volume = 289 | issue = 33 | pages = 23086–96 | date = Aug 2014 | pmid = 24990953 | doi = 10.1074/jbc.M114.570911 | pmc=4132807}}
8. ^{{cite journal | vauthors = Hoffmann H, Schiene-Fischer C | title = Functional aspects of extracellular cyclophilins | journal = Biological Chemistry | volume = 395 | issue = 7–8 | pages = 721–35 | date = Jul 2014 | pmid = 24713575 | doi = 10.1515/hsz-2014-0125 }}
9. ^1 2 3 4 5 6 {{cite journal | vauthors = Yamaguchi R, Hosaka M, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T | title = Cyclophilin C-associated protein regulation of phagocytic functions via NFAT activation in macrophages | journal = Brain Research | volume = 1397 | pages = 55–65 | date = Jun 2011 | pmid = 21435337 | doi = 10.1016/j.brainres.2011.03.036 }}
10. ^{{cite journal | vauthors = Obermayr E, Castillo-Tong DC, Pils D, Speiser P, Braicu I, Van Gorp T, Mahner S, Sehouli J, Vergote I, Zeillinger R | title = Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance -- a study of the OVCAD consortium | journal = Gynecologic Oncology | volume = 128 | issue = 1 | pages = 15–21 | date = Jan 2013 | pmid = 23017820 | doi = 10.1016/j.ygyno.2012.09.021 }}
11. ^1 {{cite journal | vauthors = Trahey M, Weissman IL | title = Cyclophilin C-associated protein: a normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 3006–11 | date = Mar 1999 | pmid = 10077627 | doi=10.1073/pnas.96.6.3006 | pmc=15885}}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Friedman J, Weissman I | title = 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 | journal = Cell | volume = 66 | issue = 4 | pages = 799–806 | date = Aug 1991 | pmid = 1652374 | doi = 10.1016/0092-8674(91)90123-G }}
  • {{cite journal | vauthors = Price ER, Jin M, Lim D, Pati S, Walsh CT, McKeon FD | title = Cyclophilin B trafficking through the secretory pathway is altered by binding of cyclosporin A | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 9 | pages = 3931–5 | date = Apr 1994 | pmid = 7909608 | pmc = 43696 | doi = 10.1073/pnas.91.9.3931 }}
  • {{cite journal | vauthors = Friedman J, Trahey M, Weissman I | title = Cloning and characterization of cyclophilin C-associated protein: a candidate natural cellular ligand for cyclophilin C | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 14 | pages = 6815–9 | date = Jul 1993 | pmid = 8341703 | pmc = 47023 | doi = 10.1073/pnas.90.14.6815 }}
  • {{cite journal | vauthors = Montague JW, Hughes FM, Cidlowski JA | title = Native recombinant cyclophilins A, B, and C degrade DNA independently of peptidylprolyl cis-trans-isomerase activity. Potential roles of cyclophilins in apoptosis | journal = The Journal of Biological Chemistry | volume = 272 | issue = 10 | pages = 6677–84 | date = Mar 1997 | pmid = 9045699 | doi = 10.1074/jbc.272.10.6677 }}
  • {{cite journal | vauthors = Trahey M, Weissman IL | title = Cyclophilin C-associated protein: a normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 3006–11 | date = Mar 1999 | pmid = 10077627 | pmc = 15885 | doi = 10.1073/pnas.96.6.3006 }}
  • {{cite journal | vauthors = 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 | title = A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration | journal = Cell | volume = 125 | issue = 4 | pages = 801–14 | date = May 2006 | pmid = 16713569 | doi = 10.1016/j.cell.2006.03.032 }}
  • {{cite journal |vauthors=Davis TL, Walker JR, Campagna-Slater V, etal |title=Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases |journal=PLoS Biol. |volume=8 |issue= 7 |pages= e1000439 |year= 2010 |pmid= 20676357 |doi= 10.1371/journal.pbio.1000439 | pmc=2911226}}
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