PPIC

For the institution with the same initialism, see 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.^[5][6][7] 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.^{[8][9][10][11]}

PPIC
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2ESL
Identifiers
Aliases	PPIC, CYPC, peptidylprolyl isomerase C
External IDs	OMIM: 123842; MGI: 97751; HomoloGene: 727; GeneCards: PPIC; OMA:PPIC - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q23.2 Start 123,023,250 bp[1] End 123,036,725 bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band 18|18 D1 Start 53,539,404 bp[2] End 53,551,187 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tibia tendon of biceps brachii skin of hip gums gingival epithelium pancreatic ductal cell mucosa of sigmoid colon periodontal fiber palpebral conjunctiva parotid gland Top expressed in molar calvaria body of femur dermis endothelial cell of lymphatic vessel efferent ductule atrium atrioventricular valve left lung lobe endocardial cushion More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cyclosporin A binding protein binding isomerase activity peptidyl-prolyl cis-trans isomerase activity unfolded protein binding Cellular component cytoplasm extracellular exosome Biological process protein folding protein peptidyl-prolyl isomerization protein refolding Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5480 19038 Ensembl ENSG00000168938 ENSMUSG00000024538 UniProt P45877 P30412 RefSeq (mRNA) NM_000943 NM_008908 RefSeq (protein) NP_000934 NP_032934 Location (UCSC) Chr 5: 123.02 – 123.04 Mb Chr 18: 53.54 – 53.55 Mb PubMed search [3] [4]
Wikidata
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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.^[10] 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.^[6]

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.^[7] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.^[8][12] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn).^[8][10] As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within the cell or secreted by the cell.^[9] In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types, though PPIC especially is highly expressed in kidney.^[9][10][13] In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation.^[8][9][10] 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.^[11] In the brain, PPIC complexes with cyclophilin C-associated protein (CyCAP) to activate microglia and macrophage function via the calcineurin/NFAT pathway.^[13]

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.^[9]

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.^[9] Similarly, PPIC may confer neuroprotection by forming a complex with CyCAP to activate survival mechanisms and mitigate ischemic damage in the brain.^[13]

Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated.^[9] 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.^[14]

Interactions

PPIC has been shown to interact with:

• CsA,^[13][15]
• CyCAP,^[13][15]
• calcineurin,^[13] and
• NFATc1.^[13]