Peptidylprolyl isomerase D

Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is an is_associated_with::enzyme which in humans is encoded by the PPID is_associated_with::gene on chromosome 4. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the is_associated_with::cis-trans is_associated_with::isomerization of proline imidic is_associated_with::peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPID participates in many biological processes, including mitochondrial is_associated_with::metabolism, is_associated_with::apoptosis, is_associated_with::redox, and is_associated_with::inflammation, as well as in related diseases and conditions, such as is_associated_with::ischemic reperfusion injury, is_associated_with::AIDS, and is_associated_with::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 is_associated_with::PPIF, FKBP51, and is_associated_with::FKBP52, 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 is_associated_with::proline imidic peptide bonds in is_associated_with::oligopeptides and accelerate the folding of proteins. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved. The PPIase family is further divided into three structurally distinct subfamilies: is_associated_with::cyclophilin (CyP), FK506-binding protein (is_associated_with::FKBP), and is_associated_with::parvulin (Pvn). As a cyclophilin, PPID binds is_associated_with::cyclosporin A (CsA) and can be found within in 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 is_associated_with::Hsp90, as well as the nuclear localization of glucocorticoid, estrogen and progesterone receptors. Along with PPIF, PPID regulates mitochondrial apoptosis. In response to elevated is_associated_with::reactive oxygen species (ROS) and calcium ion levels, PPID interacts with Bax to promote mitochondrial pore formation, thus releasing pro-apoptotic factors such as is_associated_with::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