PPIB

Peptidylprolyl isomerase B (cyclophilin B)

PDB rendering based on 1cyn.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PPIB ; CYP-S1; CYPB; HEL-S-39; OI9; SCYLP
External IDs OMIM: 123841 MGI: 97750 HomoloGene: 726 ChEMBL: 2075 GeneCards: PPIB Gene
EC number 5.2.1.8
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 5479 19035
Ensembl ENSG00000166794 ENSMUSG00000032383
UniProt P23284 P24369
RefSeq (mRNA) NM_000942 NM_011149
RefSeq (protein) NP_000933 NP_035279
Location (UCSC) Chr 15:
64.16 – 64.16 Mb		 Chr 9:
66.06 – 66.07 Mb
PubMed search

Peptidyl-prolyl cis-trans isomerase B is an enzyme that in humans is encoded by the PPIB gene.[1] 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 regulate protein folding of type I collagen.[2][3] PPIB localizes to the endoplasmic reticulum (ER) and 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] It is also associated with viral infections.[3]

Structure

Like other cyclophilins, PPIB 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] In particular, PPIB is a 21 kDa protein which contains a C-terminal ER retention motif that directs the protein to the ER organelle, while its N-terminal extension attaches it to its substrates.[3][4]

Function

PPIB is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds and regulate protein folding and maturation. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved. PPIB is the second of 18 cyclophilins to be identified in humans, after CypA.[2][3] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn).[2][6] As a cyclophilin, PPIB binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell.[4] In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types.[4][6] In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation.[2][4][6] Along with PPIC, PPIB localizes to the endoplasmic reticulum (ER), where it maintains redox homeostasis. Depletion of these two cyclophilins leads to hyperoxidation of the ER.[7]

In the ER, PPIB interacts with proteins such as P3H1, CRTAP, BiP, GRP94, PDI, and calreticulin to form foldase and chaperone complexes and facilitate protein folding, especially for type I collagen.[8][9] This protein is the major PPIase for type I collagen, since the collagen contains an abundance of prolines that require cis-trans isomerization for proper folding. Thus, PPIB is essential for collagen biosynthesis and post-translational modification and affects fibril assembly, matrix cross-linking, and bone mineralization.[8]

In addition, it is associated with the secretory pathway and released in biological fluids. This protein can bind to cells derived from T- and B-lymphocytes, and may regulate cyclosporine A-mediated immunosuppression.[10] In one experiment, the addition of PPIB into cell cultures in vitro induced chemotaxis and integrin-mediated adhesion of T cells to the extracellular matrix (ECM), suggesting that it might function in innate immunity by recruing T cells into infected tissue in vivo.[4]

Clinical significance

As a cyclophilin, PPIB 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.[4]

PPIB contributes to the replication and infection of viruses causing diseases such as AIDS, hepatitis C, measles, and influenza A. Thus, therapeutic targeting of PPIB with selective inhibitors may prove effective in combating viral infections and inflammation.[3] Currently, PPIB is employed as a biomarker for various types of cancer.[5] Moreover, there are two antigenic epitopes (CypB84-92 and CypB91-99) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes which could be used as cancer vaccines, and in fact, were used to treat lung cancer in a clinical trial.[4]

Interactions

PPIB has been shown to interact with:

References

  1. ↑ Price ER, Zydowsky LD, Jin MJ, Baker CH, McKeon FD, Walsh CT (Apr 1991). "Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence". Proc Natl Acad Sci U S A 88 (5): 1903–7. doi:10.1073/pnas.88.5.1903. PMC 51134. PMID 2000394.
  2. 1 2 3 4 Kazui T, Inoue N, Yamada O, Komatsu S (Jan 1992). "Selective cerebral perfusion during operation for aneurysms of the aortic arch: a reassessment". The Annals of Thoracic Surgery 53 (1): 109–14. doi:10.1016/0003-4975(92)90767-x. PMID 1530810.
  3. 1 2 3 4 5 Hoffmann H, Schiene-Fischer C (Jul 2014). "Functional aspects of extracellular cyclophilins". Biological Chemistry 395 (7-8): 721–35. doi:10.1515/hsz-2014-0125. PMID 24713575.
  4. 1 2 3 4 5 6 7 8 Yao Q, Li M, Yang H, Chai H, Fisher W, Chen C (Mar 2005). "Roles of cyclophilins in cancers and other organ systems". World Journal of Surgery 29 (3): 276–80. doi:10.1007/s00268-004-7812-7. PMID 15706440.
  5. 1 2 Ray P, Rialon-Guevara KL, Veras E, Sullenger BA, White RR (May 2012). "Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker". The Journal of Clinical Investigation 122 (5): 1734–41. doi:10.1172/JCI62385. PMID 22484812.
  6. 1 2 3 4 Wang T, Yun CH, Gu SY, Chang WR, Liang DC (Aug 2005). "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. doi:10.1016/j.bbrc.2005.06.006. PMID 15963461.
  7. ↑ Stocki P, Chapman DC, Beach LA, Williams DB (Aug 2014). "Depletion of cyclophilins B and C leads to dysregulation of endoplasmic reticulum redox homeostasis". The Journal of Biological Chemistry 289 (33): 23086–96. doi:10.1074/jbc.M114.570911. PMID 24990953.
  8. 1 2 3 4 5 6 Cabral WA, Perdivara I, Weis M, Terajima M, Blissett AR, Chang W, Perosky JE, Makareeva EN, Mertz EL, Leikin S, Tomer KB, Kozloff KM, Eyre DR, Yamauchi M, Marini JC (Jun 2014). "Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta". PLoS Genetics 10 (6): e1004465. doi:10.1371/journal.pgen.1004465. PMID 24968150.
  9. 1 2 3 Ishikawa Y, Bächinger HP (Nov 2013). "An additional function of the rough endoplasmic reticulum protein complex prolyl 3-hydroxylase 1·cartilage-associated protein·cyclophilin B: the CXXXC motif reveals disulfide isomerase activity in vitro". The Journal of Biological Chemistry 288 (44): 31437–46. doi:10.1074/jbc.M113.498063. PMID 24043621.
  10. ↑ "Entrez Gene: PPIB peptidylprolyl isomerase B (cyclophilin B)".
  11. ↑ Zhang J, Herscovitz H (Feb 2003). "Nascent lipidated apolipoprotein B is transported to the Golgi as an incompletely folded intermediate as probed by its association with network of endoplasmic reticulum molecular chaperones, GRP94, ERp72, BiP, calreticulin, and cyclophilin B". J. Biol. Chem. 278 (9): 7459–68. doi:10.1074/jbc.M207976200. PMID 12397072.

Further reading

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