|peptidylprolyl isomerase A (cyclophilin A)|
Ribbon diagram of cyclophilin A in complex with ciclosporin (yellow). From .
|Locus||Chr. 7 p13|
x-ray structure of peptidyl-prolyl cis-trans isomerase a, ppia, rv0009, from mycobacterium tuberculosis.
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. 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. Major isoforms have been found throughout the cell, including the ER, 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 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. 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.
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Human genes encoding proteins containing the cyclophilin type peptidyl-prolyl cis-trans isomerase domain include:
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- 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.
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- 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 . 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.
- J&J targets degenerative diseases in cyclophilin inhibitor partnership. Dan Stanton. 08-Dec-2015