Biology:Peptidylprolyl isomerase D

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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. 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.

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. PPID in particular is composed of 370 residues and shares structural homology with PPIF, FKBP4, and FKBP5, including an N-terminal immunophilin-like domain and a C-terminal tetratricopeptide repeat (TPR) domain.

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 archaea, and thus are highly conserved. The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn). As a cyclophilin, PPID 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. In addition to PPIase and protein chaperone activities, cyclophilins also function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation. 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.

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. 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.

Interactions

PPID has been shown to interact with:

• CsA
• Bax

Further reading

• "Regulation of vegetative phase change in Arabidopsis thaliana by cyclophilin 40". Science 291 (5512): 2405–7. Mar 2001. doi:10.1126/science.1057144. PMID 11264535. Bibcode: 2001Sci...291.2405B. 
• "Isolation and characterization of a 40-kDa cyclophilin-related protein". The Journal of Biological Chemistry 267 (8): 5503–7. Mar 1992. doi:10.1016/S0021-9258(18)42795-0. PMID 1544925. 
• "Expression of human cyclophilin-40 and the effect of the His141-->Trp mutation on catalysis and cyclosporin A binding". European Journal of Biochemistry 229 (1): 188–93. Apr 1995. doi:10.1111/j.1432-1033.1995.tb20454.x. PMID 7744028. 
• "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. Jun 1993. doi:10.1016/S0021-9258(18)31389-9. PMID 8509368. 
• "The structure and complete nucleotide sequence of the human cyclophilin 40 (PPID) gene". Genomics 35 (3): 448–55. Aug 1996. doi:10.1006/geno.1996.0384. PMID 8812478. 
• "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. Sep 1996. doi:10.1101/gr.6.9.791. PMID 8889548. 
• "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. Jun 1997. doi:10.1074/jbc.272.26.16224. PMID 9195923. 
• "Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90". The Journal of Biological Chemistry 273 (29): 18007–10. Jul 1998. doi:10.1074/jbc.273.29.18007. PMID 9660753. 
• "Human cyclophilin 40 is a heat shock protein that exhibits altered intracellular localization following heat shock". Cell Stress & Chaperones 6 (1): 59–70. Jan 2001. PMID 11525244. 
• "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. Oct 2002. doi:10.1074/jbc.M207097200. PMID 12145316. 
• "Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore". The Biochemical Journal 367 (Pt 2): 541–8. Oct 2002. doi:10.1042/BJ20011672. PMID 12149099. 
• "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nature Biotechnology 21 (5): 566–9. May 2003. doi:10.1038/nbt810. PMID 12665801. 
• "Cyclophilin D, a component of the permeability transition-pore, is an apoptosis repressor". Cancer Research 64 (1): 85–93. Jan 2004. doi:10.1158/0008-5472.CAN-03-0476. PMID 14729611. 
• "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 (1): 182–5. Dec 2003. doi:10.1196/annals.1299.031. PMID 15033717. Bibcode: 2003NYASA1010..182M. 
• "Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70". Cell Stress & Chaperones 9 (2): 167–81. 2005. doi:10.1379/CSC-26R.1. PMID 15497503. 
• "High-throughput mapping of a dynamic signaling network in mammalian cells". Science 307 (5715): 1621–5. Mar 2005. doi:10.1126/science.1105776. PMID 15761153. Bibcode: 2005Sci...307.1621B. 
• "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. May 2006. doi:10.1074/jbc.M513297200. PMID 16551620. 
• "The chaperone function of cyclophilin 40 maps to a cleft between the prolyl isomerase and tetratricopeptide repeat domains". FEBS Letters 580 (11): 2761–8. May 2006. doi:10.1016/j.febslet.2006.04.039. PMID 16650407.