{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc}} {{Infobox gene}} '''Peptidylprolyl isomerase A''' (PPIA), also known as '''cyclophilin A''' (CypA) or '''rotamase A''' is an enzyme that in humans is encoded by the ''PPIA'' gene on chromosome 7.<ref name = "entrez">{{cite web | title = Entrez Gene: PPIA peptidylprolyl isomerase A (cyclophilin A)| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5478}}</ref><ref name="pmid2197089">{{cite journal | vauthors = Haendler B, Hofer E | title = Characterization of the human cyclophilin gene and of related processed pseudogenes | journal = European Journal of Biochemistry | volume = 190 | issue = 3 | pages = 477–82 | date = Jul 1990 | pmid = 2197089 | doi = 10.1111/j.1432-1033.1990.tb15598.x }}</ref><ref name="pmidpmid1989998">{{cite journal | vauthors = Holzman TF, Egan DA, Edalji R, Simmer RL, Helfrich R, Taylor A, Burres NS | title = Preliminary characterization of a cloned neutral isoelectric form of the human peptidyl prolyl isomerase cyclophilin | journal = The Journal of Biological Chemistry | volume = 266 | issue = 4 | pages = 2474–9 | date = Feb 1991 | doi = 10.1016/S0021-9258(18)52268-7 | pmid = 1989998 | doi-access = free }}</ref> 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 many biological processes, including intracellular signaling, transcription, inflammation, and apoptosis.<ref name = "entrez"/><ref name = "pmid1530810">{{cite journal | vauthors = Kazui T, Inoue N, Yamada O, Komatsu S | title = Selective cerebral perfusion during operation for aneurysms of the aortic arch: a reassessment | journal = The Annals of Thoracic Surgery | volume = 53 | issue = 1 | pages = 109–14 | date = Jan 1992 | pmid = 1530810 | doi=10.1016/0003-4975(92)90767-x| doi-access = free }}</ref><ref name = "pmid24502618">{{cite journal | vauthors = Ramachandran S, Venugopal A, Kutty VR, A V, G D, Chitrasree V, Mullassari A, Pratapchandran NS, Santosh KR, Pillai MR, Kartha CC | title = Plasma level of cyclophilin A is increased in patients with type 2 diabetes mellitus and suggests presence of vascular disease | journal = Cardiovascular Diabetology | volume = 13 | pages = 38 | date = 7 February 2014 | pmid = 24502618 | doi = 10.1186/1475-2840-13-38 | pmc=3922405 | doi-access = free }}</ref><ref name = "pmid23180369">{{cite journal | vauthors = Wei Y, Jinchuan Y, Yi L, Jun W, Zhongqun W, Cuiping W | title = Antiapoptotic and proapoptotic signaling of cyclophilin A in endothelial cells | journal = Inflammation | volume = 36 | issue = 3 | pages = 567–72 | date = Jun 2013 | pmid = 23180369 | doi = 10.1007/s10753-012-9578-7 | s2cid = 24968009 }}</ref><ref name = "pmid24713575">{{cite journal | vauthors = Hoffmann H, Schiene-Fischer C | title = Functional aspects of extracellular cyclophilins | journal = Biological Chemistry | volume = 395 | issue = 7–8 | pages = 721–35 | date = Jul 2014 | pmid = 24713575 | doi = 10.1515/hsz-2014-0125 | s2cid = 32395688 }}</ref> Due to its various functions, PPIA has been implicated in a broad range of inflammatory diseases, including atherosclerosis and arthritis, and viral infections.<ref name = "pmid24502618"/><ref name = "pmid23180369"/><ref name = "pmid24713575"/>
==Structure==
PPIA is an 18 kDa, 165-amino acid long cytosolic protein.<ref name=pmid19865066>{{cite journal | vauthors = Obchoei S, Wongkhan S, Wongkham C, Li M, Yao Q, Chen C | title = Cyclophilin A: potential functions and therapeutic target for human cancer | journal = Medical Science Monitor | volume = 15 | issue = 11 | pages = RA221–32 | date = Nov 2009 | pmid = 19865066 }}</ref> Like other cyclophilins, PPIA 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.<ref name = "pmid1530810"/><ref name=pmid19865066/><ref name="pmid15963461">{{cite journal | vauthors = Wang T, Yun CH, Gu SY, Chang WR, Liang DC | title = 1.88 A crystal structure of the C domain of hCyP33: a novel domain of peptidyl-prolyl cis-trans isomerase | journal = Biochemical and Biophysical Research Communications | volume = 333 | issue = 3 | pages = 845–9 | date = Aug 2005 | pmid = 15963461 | doi = 10.1016/j.bbrc.2005.06.006 }}</ref> In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel.<ref name="pmid15963461"/> Its active site is a hydrophobic pocket that binds peptides containing proline. Cyclosporine can bind this pocket to inhibit the protein's enzymatic activity.<ref name = "pmid1530810"/>
== Function ==
This gene encodes 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 protein folding.<ref name = "entrez"/><ref name=pmid19865066/> Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.<ref name = "pmid1530810"/><ref name = "pmid24713575"/> Of the 18 known human cyclophilins, PPIA is the most abundantly expressed isozyme.<ref name = "pmid24713575"/> In particular, PPIA is predominantly expressed in the nucleus and cytoplasm of the cell, where it partakes in intracellular signaling, protein transport, and transcription regulation.<ref name = "pmid1530810"/><ref name = "pmid24502618"/><ref name = "pmid23180369"/><ref name = "pmid24713575"/><ref name=pmid19865066/> In hemopoietic cells, subcellular localization of PPIA from the nucleus to the cytoplasm has been observed during c-Jun N-terminal kinase- and serine protease-dependent microtubule disruption. This localization has been correlated with G2/M arrest, indicating that the protein's PPIase function may be regulated by microtubule dynamics during the cell cycle.<ref name=pmid19865066/> PPIA has also been associated with the mitochondria.<ref name="pmid23589362">{{cite journal | vauthors = Ye Y, Huang A, Huang C, Liu J, Wang B, Lin K, Chen Q, Zeng Y, Chen H, Tao X, Wei G, Wu Y | title = Comparative mitochondrial proteomic analysis of hepatocellular carcinoma from patients | journal = Proteomics – Clinical Applications| volume = 7 | issue = 5–6 | pages = 403–15 | year = 2013 | pmid = 23589362 | doi = 10.1002/prca.201100103 | s2cid = 5906425 }}</ref>
Moreover, the enzyme participates in inflammatory and apoptotic processes in extracellular settings. In the presence of reactive oxygen species (ROS), vascular smooth muscle cells (VSMCs), monocytes/macrophages, and endothelial cells (ECs) secrete PPIA to induce an inflammatory response and mitigate tissue injury.<ref name = "pmid24502618"/><ref name = "pmid23180369"/><ref name=pmid19865066/><ref name="pmid15706440">{{cite journal | vauthors = Yao Q, Li M, Yang H, Chai H, Fisher W, Chen C | title = Roles of cyclophilins in cancers and other organ systems | journal = World Journal of Surgery | volume = 29 | issue = 3 | pages = 276–80 | date = Mar 2005 | pmid = 15706440 | doi = 10.1007/s00268-004-7812-7 | s2cid = 11678319 }}</ref> PPIA may also activate Akt and NF-κB signaling, resulting in the upregulation of Bcl-2, an antiapoptotic protein, and thus preventing apoptosis in ECs in response to oxidative stress.<ref name = "pmid23180369"/> PPIA may also regulate ERK1/2, JNK, p38 kinase, Akt, and IκB signalling pathways through activating the CD147 receptor.<ref name=pmid19865066/> PPIA-mediated activation of the ERK, JNK, and p38 kinase pathways also contributes to angiogenesis.<ref name=pmid19865066/> Additionally, PPIA induces cell migration and proliferation in smooth muscle.<ref name = "pmid24502618"/> In the case of T cells, PPIA regulates the T-cell-specific tyrosine kinase ITK upon T-cell receptor stimulation.<ref name = "pmid24713575"/>
== Clinical significance ==
The PPIA protein is an important apoptotic constituent. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.<ref>{{cite journal | vauthors = Kerr JF, Wyllie AH, Currie AR | title = Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics | journal = British Journal of Cancer | volume = 26 | issue = 4 | pages = 239–57 | date = Aug 1972 | pmid = 4561027 | doi=10.1038/bjc.1972.33 | pmc=2008650}}</ref> It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
As a proinflammatory cytokine, PPIA is highly involved in acute and chronic inflammatory diseases, including sepsis, atherosclerosis, and rheumatoid arthritis.<ref name = "pmid24502618"/><ref name = "pmid23180369"/><ref name = "pmid24713575"/> Thus, therapeutic targeting of PPIA with selective inhibitors may prove effective in combatting such inflammatory diseases and symptoms.<ref name = "pmid23180369"/><ref name = "pmid24713575"/> Correlation between plasma PPIA levels and hyperglycemia symptoms also promotes utilization of PPIA as a biomarker for diabetes and vascular disease.<ref name = "pmid24502618"/>
Furthermore, PPIA is involved in cerebral hypoxia-ischemia by contributing to the nuclear transport of AIF, a proapoptotic factor, in neurons.<ref name = "pmid24713575"/> To maintain the integrity of the blood brain barrier and mitigate brain injury, PPIA helps to recruit circulating monocytes and stimulates survival and growth pathways.<ref name = "pmid24502618"/> 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, PPIA expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated.<ref name=pmid19865066/><ref name="pmid15706440"/> PPIA overexpression has been associated with hepatocellular carcinoma, lung cancer, pancreatic adenocarcinoma, endometrial carcinoma, esophageal squamous cell carcinoma, and melanoma.<ref name=pmid19865066/><ref name=pmid23589362/>
The protein can also interact with several HIV proteins, including p55 gag, Vpr, and capsid protein, and has been shown to be necessary for the formation of infectious HIV virions.<ref name = "entrez"/><ref>{{cite journal | vauthors = Agarwal, PK | title = Cis/trans isomerization in HIV-1 capsid protein catalyzed by cyclophilin A: insights from computational and theoretical studies | journal = Proteins | volume = 56 | issue = 3 | pages = 449–63 | date = Aug 2004 | pmid = 15229879 | doi=10.1002/prot.20135 | s2cid = 19907859 }}</ref> As a result, PPIA contributes to viral diseases such as AIDS, hepatitis C, measles, and influenza A.<ref name = "pmid24713575"/>
== Interactions ==
Peptidylprolyl isomerase A has been shown to interact with: * ITK,<ref name=pmid11830645>{{cite journal | vauthors = Brazin KN, Mallis RJ, Fulton DB, Andreotti AH | title = Regulation of the tyrosine kinase Itk by the peptidyl-prolyl isomerase cyclophilin A | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 4 | pages = 1899–904 | date = Feb 2002 | pmid = 11830645 | pmc = 122291 | doi = 10.1073/pnas.042529199 | bibcode = 2002PNAS...99.1899B | doi-access = free }}</ref> * CD147,<ref name = "pmid24502618"/><ref name=pmid19865066/> * P53,<ref name = "pmid24713575"/> * STAT3,<ref name = "pmid24713575"/>
== See also ==
== References == {{reflist|33em}}
== Further reading == {{refbegin|33em}} * {{cite book | vauthors = Franke EK, Luban J | title = Cell Activation and Apoptosis in HIV Infection | chapter = Cyclophilin and Gag in HIV-1 Replication and Pathogenesis | volume = 374 | pages = [https://archive.org/details/cellactivationap00jean/page/217 217–28] | year = 1995 | pmid = 7572395 | doi = 10.1007/978-1-4615-1995-9_19 | isbn = 978-0-306-45063-1 | series = Advances in Experimental Medicine and Biology | publisher = Springer | chapter-url-access = registration | chapter-url = https://archive.org/details/cellactivationap00jean/page/217 }} * {{cite journal | vauthors = Sokolskaja E, Luban J | title = Cyclophilin, TRIM5, and innate immunity to HIV-1 | journal = Current Opinion in Microbiology | volume = 9 | issue = 4 | pages = 404–8 | date = Aug 2006 | pmid = 16815734 | doi = 10.1016/j.mib.2006.06.011 }} {{refend}}
{{PDB Gallery|geneid=5478}}