Cyclophilin Explained

Symbol:Pro_isomerase
Cyclophilin type peptidyl-prolyl cis-trans isomerase/CLD
Pfam:PF00160
Pfam Clan:CL0475
Interpro:IPR002130
Prosite:PDOC00154
Scop:1cyh

Cyclophilins (CYPs) are a family of proteins named after their ability to bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants.[1] They are found in all domains of life. These proteins have peptidyl prolyl isomerase activity, which catalyzes the isomerization of peptide bonds from trans form to cis form at proline residues and facilitates protein folding.

Cyclophilin A is a cytosolic and highly abundant protein. The protein belongs to a family of isozymes, including cyclophilins B and C, and natural killer cell cyclophilin-related protein.[2] [3] [4] Major isoforms have been found within single cells, including inside the Endoplasmic reticulum, and some are even secreted.

Mammalian cyclophilins

Human genes encoding proteins containing the cyclophilin domain include:

Cyclophilin A

Cyclophilin A (CYPA) also known as peptidylprolyl isomerase A (PPIA), which is found in the cytosol, has a beta barrel structure with two alpha helices and a beta-sheet. Other cyclophilins have similar structures to cyclophilin A. The cyclosporin-cyclophilin A complex inhibits a calcium/calmodulin-dependent phosphatase, calcineurin, the inhibition of which is thought to suppress organ rejection by halting the production of the pro-inflammatory molecules TNF alpha and interleukin 2.

Cyclophilin A is also known to be recruited by the Gag polyprotein during HIV-1 virus infection, and its incorporation into new virus particles is essential for HIV-1 infectivity.[5]

Cyclophilin D

Cyclophilin D (PPIF, note that literature is confusing, the mitochondrial cyclophilin is encoded by the PPIF gene), which is located in the matrix of mitochondria, is only a modulatory, but may or may not be a structural component of the mitochondrial permeability transition pore.[6] [7] The pore opening raises the permeability of the mitochondrial inner membrane, allows influx of cytosolic molecules into the mitochondrial matrix, increases the matrix volume, and disrupts the mitochondrial outer membrane. As a result, the mitochondria fall into a functional disorder, so the opening of the pore plays an important role in cell death. Cyclophilin D is thought to regulate the opening of the pore because cyclosporin A, which binds to CyP-D, inhibits the pore opening.

However, mitochondria obtained from the cysts of Artemia franciscana, do not exhibit the mitochondrial permeability transition pore [8] [9]

Clinical significance

Diseases

Overexpression of Cyclophilin A has been linked to poor response to inflammatory diseases, the progression or metastasis of cancer, and aging.[10]

Cyclophilins as drug targets

Cyclophilin inhibitors, such as cyclosporin, are being developed to treat neurodegenerative diseases.[11] Cyclophilin inhibition may also be a therapy for liver diseases.[12]

Notes and References

  1. Stamnes MA, Rutherford SL, Zuker CS . Cyclophilins: a new family of proteins involved in intracellular folding . Trends Cell Biol. . 2 . 9 . 272–6 . September 1992 . 14731520 . 10.1016/0962-8924(92)90200-7.
  2. Trandinh CC, Pao GM, Saier MH . Structural and evolutionary relationships among the immunophilins: two ubiquitous families of peptidyl-prolyl cis-trans isomerases . FASEB J. . 6 . 15 . 3410–20 . December 1992 . 1464374 . 10.1096/fasebj.6.15.1464374. free . 30435500 .
  3. Galat A . Peptidylproline cis-trans-isomerases: immunophilins . Eur. J. Biochem. . 216 . 3 . 689–707 . September 1993 . 8404888 . 10.1111/j.1432-1033.1993.tb18189.x. free .
  4. Hacker J, Fischer G . Immunophilins: structure-function relationship and possible role in microbial pathogenicity . Mol. Microbiol. . 10 . 3 . 445–56 . November 1993 . 7526121 . 10.1111/j.1365-2958.1993.tb00917.x. 13160331 .
  5. 7969495 . 10.1038/372363a0 . 372 . 6504 . Functional association of cyclophilin A with HIV-1 virions . 24 November 1994 . Nature . 363–365 . Thali M, Bukovsky A, Kondo E. 1994Natur.372..363T . 4371206 . etal.
  6. 15792954 . 10.1074/jbc.C500089200 . 280 . 19 . Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D . May 2005 . J. Biol. Chem. . 18558–61 . Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P. free . 11577/1474540 . free .
  7. 21173147 . 10.1074/jbc.M110.196600 . 3057831 . 286 . 8 . Complex contribution of cyclophilin D to Ca2+-induced permeability transition in brain mitochondria, with relation to the bioenergetic state . February 2011 . J. Biol. Chem. . 6345–53 . Doczi J, Turiák L, Vajda S. etal. free .
  8. 15718386 . 10.1152/ajpregu.00844.2004 . 289 . 1 . Mitochondrial permeability transition in the crustacean Artemia franciscana: absence of a calcium-regulated pore in the face of profound calcium storage . July 2005 . Am. J. Physiol. Regul. Integr. Comp. Physiol. . R68–76 . Menze MA, Hutchinson K, Laborde SM, Hand SC. 8352110 .
  9. 21205213 . 10.1111/j.1742-4658.2010.08001.x . 278 . 5 . A distinct sequence in the adenine nucleotide translocase from Artemia franciscana embryos is associated with insensitivity to bongkrekate and atypical effects of adenine nucleotides on Ca2+ uptake and sequestration . March 2011 . FEBS J. . 822–36 . Konràd C, Kiss G, Töröcsik B. etal. free .
  10. Cyclophilin A: a key player for human disease. P . Nigro. G . Pompilio . M C . Capogrossi. Cell Death and Disease. 4. 2013. 10 . e888 . 10.1038/cddis.2013.410 . 24176846 . 3920964 .
  11. http://www.in-pharmatechnologist.com/Drug-Delivery/J-J-targets-degenerative-diseases-in-cyclophilin-inhibitor-partnership/ J&J targets degenerative diseases in cyclophilin inhibitor partnership. Dan Stanton. 08-Dec-2015
  12. Cyclophilin inhibition as potential therapy for liver diseases. Journal of Hepatology. 61. 5. November 2014. 1166–1174. 10.1016/j.jhep.2014.07.008. 25048953. Naoumov. Nikolai V.. free.

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