Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is an enzyme which in humans is encoded by the PPIDgene on chromosome 4. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-transisomerization 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]
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]
↑ 2.02.12.22.3Kazui 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. PMID1530810.
↑ 4.04.14.24.34.4Wang 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. PMID15963461.
↑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. PMID24713575.
Further reading
Berardini TZ, Bollman K, Sun H, Poethig RS (Mar 2001). "Regulation of vegetative phase change in Arabidopsis thaliana by cyclophilin 40". Science. 291 (5512): 2405–7. doi:10.1126/science.1057144. PMID11264535.
Kieffer LJ, Thalhammer T, Handschumacher RE (Mar 1992). "Isolation and characterization of a 40-kDa cyclophilin-related protein". The Journal of Biological Chemistry. 267 (8): 5503–7. PMID1544925.
Hoffmann K, Kakalis LT, Anderson KS, Armitage IM, Handschumacher RE (Apr 1995). "Expression of human cyclophilin-40 and the effect of the His141-->Trp mutation on catalysis and cyclosporin A binding". European Journal of Biochemistry / FEBS. 229 (1): 188–93. doi:10.1111/j.1432-1033.1995.tb20454.x. PMID7744028.
Kieffer LJ, Seng TW, Li W, Osterman DG, Handschumacher RE, Bayney RM (Jun 1993). "Cyclophilin-40, a protein with homology to the P59 component of the steroid receptor complex. Cloning of the cDNA and further characterization". The Journal of Biological Chemistry. 268 (17): 12303–10. PMID8509368.
Yokoi H, Shimizu Y, Anazawa H, Lefebvre CA, Korneluk RG, Ikeda JE (Aug 1996). "The structure and complete nucleotide sequence of the human cyclophilin 40 (PPID) gene". Genomics. 35 (3): 448–55. doi:10.1006/geno.1996.0384. PMID8812478.
Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID8889548.
Silverstein AM, Galigniana MD, Chen MS, Owens-Grillo JK, Chinkers M, Pratt WB (Jun 1997). "Protein phosphatase 5 is a major component of glucocorticoid receptor.hsp90 complexes with properties of an FK506-binding immunophilin". The Journal of Biological Chemistry. 272 (26): 16224–30. doi:10.1074/jbc.272.26.16224. PMID9195923.
Young JC, Obermann WM, Hartl FU (Jul 1998). "Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90". The Journal of Biological Chemistry. 273 (29): 18007–10. doi:10.1074/jbc.273.29.18007. PMID9660753.
Ward BK, Allan RK, Mok D, Temple SE, Taylor P, Dornan J, Mark PJ, Shaw DJ, Kumar P, Walkinshaw MD, Ratajczak T (Oct 2002). "A structure-based mutational analysis of cyclophilin 40 identifies key residues in the core tetratricopeptide repeat domain that mediate binding to Hsp90". The Journal of Biological Chemistry. 277 (43): 40799–809. doi:10.1074/jbc.M207097200. PMID12145316.
Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J (May 2003). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nature Biotechnology. 21 (5): 566–9. doi:10.1038/nbt810. PMID12665801.
Schubert A, Grimm S (Jan 2004). "Cyclophilin D, a component of the permeability transition-pore, is an apoptosis repressor". Cancer Research. 64 (1): 85–93. doi:10.1158/0008-5472.CAN-03-0476. PMID14729611.
Machida K, Osada H (Dec 2003). "Molecular interaction between cyclophilin D and adenine nucleotide translocase in cytochrome c release: does it determine whether cytochrome c release is dependent on permeability transition or not?". Annals of the New York Academy of Sciences. 1010: 182–5. doi:10.1196/annals.1299.031. PMID15033717.
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. PMID15761153.
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. PMID16551620.
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. PMID16650407.
