PPIC

{{Short description|Protein-coding gene in the species Homo sapiens}}

{{For|the institution with the same initialism|Public Policy Institute of California}}

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.{{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 | doi = 10.1016/0378-1119(92)90097-9 }}{{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 | doi = 10.1021/bi00193a007 }}{{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}} 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.{{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| doi-access = free }}{{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 | s2cid = 11678319 }}{{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 }}{{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| doi-access = free }}

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. 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.

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. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.{{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 | s2cid = 32395688 }} The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn). As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within the cell or secreted by the cell. In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types, though PPIC especially is highly expressed in kidney.{{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 | s2cid = 28737748 }} In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation. 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. In the brain, PPIC complexes with cyclophilin C-associated protein (CyCAP) to activate microglia and macrophage function via the calcineurin/NFAT pathway.

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.

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. Similarly, PPIC may confer neuroprotection by forming a complex with CyCAP to activate survival mechanisms and mitigate ischemic damage in the brain.

Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated. 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.{{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 }}

Interactions

PPIC has been shown to interact with:

CsA,{{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| bibcode = 1999PNAS...96.3006T | doi-access = free }}
CyCAP,
calcineurin, and
NFATc1.

PPIC

Structure

Function

Clinical Significance

Interactions

References

Further reading