Cyclophilin

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.

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. 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

Clinical significance

Diseases

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

Cyclophilins as drug targets

Cyclophilin inhibitors, such as cyclosporin, are being developed to treat neurodegenerative diseases. Cyclophilin inhibition may also be a therapy for liver diseases. A review from 2024 discussed cyclophilins as conserved and relevant for protein folding and cellular signaling. The review summarized the involvement of Cyps in viral replication and cancer progression. Specifically, CypA is mentioned for its key role in the replication of human pathogens such as HIV-1. Cyp inhibition is promising for reducing infectivity of viruses and as a tumor suppressor.

References

References

1. (September 1992). "Cyclophilins: a new family of proteins involved in intracellular folding". Trends Cell Biol..
2. (December 1992). "Structural and evolutionary relationships among the immunophilins: two ubiquitous families of peptidyl-prolyl cis-trans isomerases". FASEB J..
3. Galat A. (September 1993). "Peptidylproline cis-trans-isomerases: immunophilins". Eur. J. Biochem..
4. (November 1993). "Immunophilins: structure-function relationship and possible role in microbial pathogenicity". Mol. Microbiol..
5. (24 November 1994). "Functional association of cyclophilin A with HIV-1 virions". Nature.
6. (May 2005). "Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D". J. Biol. Chem..
7. (February 2011). "Complex contribution of cyclophilin D to Ca2+-induced permeability transition in brain mitochondria, with relation to the bioenergetic state". J. Biol. Chem..
8. (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..
9. (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..
10. (2013). "Cyclophilin A: a key player for human disease". Cell Death and Disease.
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. (November 2014). "Cyclophilin inhibition as potential therapy for liver diseases". Journal of Hepatology.
13. Winston T. Stauffer. (26 October 2025). "Cyclophilin inhibition as a strategy for the treatment of human disease". Frontiers of Pharmacology.