Peptidylprolyl isomerase D

For other uses of the acronym PPID, see PPID.
Peptidylprolyl isomerase D

PDB rendering based on 1ihg.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PPID ; CYP-40; CYPD
External IDs OMIM: 601753 MGI: 1914988 HomoloGene: 31283 ChEMBL: 1697657 GeneCards: PPID Gene
EC number 5.2.1.8
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 5481 67738
Ensembl ENSG00000171497 ENSMUSG00000027804
UniProt Q08752 Q9CR16
RefSeq (mRNA) NM_005038 NM_026352
RefSeq (protein) NP_005029 NP_080628
Location (UCSC) Chr 4:
158.71 – 158.72 Mb		 Chr 3:
79.59 – 79.6 Mb
PubMed search

Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is an enzyme which in humans is encoded by the PPID gene on chromosome 4. 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] In addition, PPID 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.[2][3][4][5]

Structure

Like other cyclophilins, PPID 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.[4] PPID in particular is composed of 370 residues and shares structural homology with PPIF, FKBP51, and FKBP52, including an N-terminal immunophilin-like domain and a C-terminal tetratricopeptide repeat (TPR) domain.[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.[1] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.[2][7] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn).[2][4] As a cyclophilin, PPID binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell.[3] In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types.[3][4] In addition to PPIase and protein chaperone activities, cyclophilins also function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation.[2][3][4] PPID in particular helps chaperone the assembly of heat shock protein Hsp90, as well as the nuclear localization of glucocorticoid, estrogen and progesterone receptors. Along with PPIF, PPID regulates mitochondrial apoptosis. In response to elevated reactive oxygen species (ROS) and calcium ion levels, PPID interacts with Bax to promote mitochondrial pore formation, thus releasing pro-apoptotic factors such as cytochrome C and AIF.[6]

Clinical Significance

As a cyclophilin, PPID 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.

Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated.[3] Studies have shown that PPID protects human keratinocytes from UVA-induced apoptosis, so medication and therapies that inhibit PPID, such as CsA, may inadvertently aid skin cancer development. Conversely, treatments promoting PPID activity may improve patient outcomes when paired with UVA therapies against cancer.[6]

Interactions

PPID has been shown to interact with:

References

  1. 1 2 "Entrez Gene: PPID peptidylprolyl isomerase D (cyclophilin D)".
  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 6 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.
  4. 1 2 3 4 5 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.
  5. ↑ 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.
  6. 1 2 3 4 Jandova J, Janda J, Sligh JE (Mar 2013). "Cyclophilin 40 alters UVA-induced apoptosis and mitochondrial ROS generation in keratinocytes". Experimental Cell Research 319 (5): 750–60. doi:10.1016/j.yexcr.2012.11.016. PMID 23220213.
  7. ↑ 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.

Further reading

  • Carrello A, Allan RK, Morgan SL, Owen BA, Mok D, Ward BK, Minchin RF, Toft DO, Ratajczak T (2005). "Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70". Cell Stress & Chaperones 9 (2): 167–81. doi:10.1379/CSC-26R.1. PMC 1065296. PMID 15497503. 
  • Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, Wrana JL (Mar 2005). "High-throughput mapping of a dynamic signaling network in mammalian cells". Science 307 (5715): 1621–5. doi:10.1126/science.1105776. PMID 15761153. 
  • Machida K, Ohta Y, Osada H (May 2006). "Suppression of apoptosis by cyclophilin D via stabilization of hexokinase II mitochondrial binding in cancer cells". The Journal of Biological Chemistry 281 (20): 14314–20. doi:10.1074/jbc.M513297200. PMID 16551620. 
  • Mok D, Allan RK, Carrello A, Wangoo K, Walkinshaw MD, Ratajczak T (May 2006). "The chaperone function of cyclophilin 40 maps to a cleft between the prolyl isomerase and tetratricopeptide repeat domains". FEBS Letters 580 (11): 2761–8. doi:10.1016/j.febslet.2006.04.039. PMID 16650407. 
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