Cyclophilin type peptidyl-prolyl cis-trans isomerase/CLD
Ribbon diagram of cyclophilin A in complex with ciclosporin (yellow). From PDB: 1CWA​.
Identifiers
Symbol	Pro_isomerase
Pfam	PF00160
Pfam clan	CL0475
InterPro	IPR002130
PROSITE	PDOC00154
SCOP2	1cyh / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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:

• PPIA, PPIB, PPIC, PPID, PPIE, PPIF, PPIG, PPIH
• PPIL1, PPIL2, PPIL3, PPIL4, PPIAL4, PPIL6
• PPWD1

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]

This section needs expansion. You can help by adding to it. (December 2015)

References

External links

• Cyclophilins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)