Cyclophilin
| peptidylprolyl isomerase A (cyclophilin A) | |
|---|---|
| File:Cyclophilin A-cyclosporin complex 1CWA.png Ribbon diagram of cyclophilin A in complex with ciclosporin (yellow). From PDB: 1CWA. | |
| Identifiers | |
| Symbol | PPIA |
| Entrez | 5478 |
| HUGO | 9253 |
| OMIM | 123840 |
| RefSeq | NM_203430 |
| UniProt | Q3KQW3 |
| Other data | |
| EC number | 5.2.1.8 |
| Locus | Chr. 7 p13 |
| Pro_isomerase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| File:PDB 1w74 EBI.jpg x-ray structure of peptidyl-prolyl cis-trans isomerase a, ppia, rv0009, from mycobacterium tuberculosis. | |||||||||
| Identifiers | |||||||||
| Symbol | Pro_isomerase | ||||||||
| Pfam | PF00160 | ||||||||
| Pfam clan | CL0475 | ||||||||
| InterPro | IPR002130 | ||||||||
| PROSITE | PDOC00154 | ||||||||
| SCOP | 1cyh | ||||||||
| SUPERFAMILY | 1cyh | ||||||||
| |||||||||
Cyclophilins are a family of proteins from vertebrates and other organisms that bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants.[1] 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.
Cyclophilin A (CypA)
Cyclophilin A also known as peptidylprolyl isomerase A, 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, 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]
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Examples
Human genes encoding proteins containing the cyclophilin type peptidyl-prolyl cis-trans isomerase domain include:
References
- ↑ Stamnes MA, Rutherford SL, Zuker CS (September 1992). "Cyclophilins: a new family of proteins involved in intracellular folding". Trends Cell Biol. 2 (9): 272–6. doi:10.1016/0962-8924(92)90200-7. PMID 14731520.
- ↑ Trandinh CC, Pao GM, Saier MH (December 1992). "Structural and evolutionary relationships among the immunophilins: two ubiquitous families of peptidyl-prolyl cis-trans isomerases". FASEB J. 6 (15): 3410–20. PMID 1464374.
- ↑ Galat A (September 1993). "Peptidylproline cis-trans-isomerases: immunophilins". Eur. J. Biochem. 216 (3): 689–707. doi:10.1111/j.1432-1033.1993.tb18189.x. PMID 8404888.
- ↑ Hacker J, Fischer G (November 1993). "Immunophilins: structure-function relationship and possible role in microbial pathogenicity". Mol. Microbiol. 10 (3): 445–56. doi:10.1111/j.1365-2958.1993.tb00917.x. PMID 7526121.
- ↑ Thali M, Bukovsky A, Kondo E, et al. (24 November 1994). "Functional association of cyclophilin A with HIV-1 virions". Nature. 372 (6504): 363–365. doi:10.1038/372363a0. PMID 7969495.
- ↑ Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P (May 2005). "Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D". J. Biol. Chem. 280 (19): 18558–61. doi:10.1074/jbc.C500089200. PMID 15792954.
- ↑ Doczi J, Turiák L, Vajda S, et al. (February 2011). "Complex contribution of cyclophilin D to Ca2+-induced permeability transition in brain mitochondria, with relation to the bioenergetic state". J. Biol. Chem. 286 (8): 6345–53. doi:10.1074/jbc.M110.196600. PMC 3057831. PMID 21173147.
- ↑ Menze MA, Hutchinson K, Laborde SM, Hand SC (July 2005). "Mitochondrial permeability transition in the crustacean Artemia franciscana: absence of a calcium-regulated pore in the face of profound calcium storage". Am. J. Physiol. Regul. Integr. Comp. Physiol. 289 (1): R68–76. doi:10.1152/ajpregu.00844.2004. PMID 15718386.
- ↑ Konràd C, Kiss G, Töröcsik B, et al. (March 2011). "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". FEBS J. 278 (5): 822–36. doi:10.1111/j.1742-4658.2010.08001.x. PMID 21205213.
- ↑ Nigro, P; Pompilio, G; Capogrossi, M C (2013). "Cyclophilin A: a key player for human disease". Cell Death and Disease. 4.
- ↑ J&J targets degenerative diseases in cyclophilin inhibitor partnership. Dan Stanton. 08-Dec-2015
- ↑ "Cyclophilin inhibition as potential therapy for liver diseases". Journal of Hepatology. 61 (5): 1166–1174. November 2014.
External links
- Cyclophilins at the US National Library of Medicine Medical Subject Headings (MeSH)