Immunophilins

FKBP12, a human immunophilin. It is the target protein of tacrolimus, an immunosuppressant drug.

In molecular biology, immunophilins are a group of endogenous cytosolic peptidyl-prolyl isomerases (PPI), which catalyze the interconversion between the cis and trans isomers of peptide bonds containing the amino acid proline (Pro). They are chaperone molecules that generally assist in the proper folding of diverse "client" proteins. There are two families of immunophilins that are structurally unrelated, but have similar biochemical activity: cyclosporin-binding cyclophilins (CyPs) and FK506-binding proteins (FKBPs).[1] In 2005, a group of dual-family immunophilins (DFI) has been discovered, mostly in unicellular organisms; these DFIs are natural chimera of CyP and FKBPs, fused in either order (CyP-FKBP or FKBP-CyP).[2] Immunophilins are named as such because they were originally discovered in the context of immunosuppressive drugs; however both families of prolyl isomerases are ubiquitous across taxa and have diverse functions.[3][4]

In medicine

In medicine, immunophilins act as receptors for immunosuppressive drugs such as sirolimus (rapamycin), cyclosporin (such as CsA) and tacrolimus (FK506), which inhibit the prolyl isomerase activity of the immunophilins. The drug-immunophilin complexes (CsA-CyP and FK506-FKBP) bind to calcineurin, which inhibits the phosphatase activity of calcineurin and engenders the immunosuppressive effects.[5] CsA and FK506 thus affect the calcium-dependent step of T cell response which prevents release of interleukin-2. Immunophilins also form protein complex with ryanodine and inositol triphosphate (IP3) which impacts the release of calcium.

FK506 binds with high affinity to other smaller proteins, such as FKBP-12. FKBP-12 and cyclophilins both share common peptide-prolyl isomerase activity. While the majority of the Peptide bonds within proteins exist in trans (planar) conformation because of the partial double-bond nature of the peptide bond,[6] a small fraction occurs in cis. Unlike regular peptide bonds, the X-Pro peptide bond does not adopt the intended trans conformation spontaneously, thus, cis-trans isomerization can be the rate-limiting (slowest) step in the process of protein folding.[7] Immunophilins, with their prolyl isomerase activity, thus function as protein-folding chaperones.

See also

References

  1. ↑ Barik, S. (December 2006). "Immunophilins: for the love of proteins". Cellular and Molecular Life Sciences. 63 (24): 2889–2900. doi:10.1007/s00018-006-6215-3. ISSN 1420-682X. PMC 11136219. PMID 17075696. S2CID 26048417.
  2. ↑ Adams, Brian; Musiyenko, Alla; Kumar, Rajinder; Barik, Sailen (2005-07-01). "A novel class of dual-family immunophilins". The Journal of Biological Chemistry. 280 (26): 24308–24314. doi:10.1074/jbc.M500990200. ISSN 0021-9258. PMC 2270415. PMID 15845546.
  3. ↑ Schreiber, Stuart L. (1991-01-18). "Chemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands". Science. 251 (4991): 283–287. Bibcode:1991Sci...251..283S. doi:10.1126/science.1702904. PMID 1702904.
  4. ↑ Wang, Ping; Heitman, Joseph (2005-06-27). "The cyclophilins". Genome Biology. 6 (7): 226. doi:10.1186/gb-2005-6-7-226. ISSN 1474-760X. PMC 1175980. PMID 15998457.
  5. ↑ Ho, S.; Clipstone, N.; Timmermann, L.; Northrop, J.; Graef, I.; Fiorentino, D.; Nourse, J.; Crabtree, G. R. (September 1996). "The mechanism of action of cyclosporin A and FK506". Clinical Immunology and Immunopathology. 80 (3 Pt 2): S40–45. doi:10.1006/clin.1996.0140. ISSN 0090-1229. PMID 8811062.
  6. ↑ Ramachandran, G. N.; Sasisekharan, V. (1968). "Conformation of polypeptides and proteins". Advances in Protein Chemistry. 23: 283–438. doi:10.1016/S0065-3233(08)60402-7. ISBN 9780120342235. ISSN 0065-3233. PMID 4882249.{{cite journal}}: CS1 maint: periodical has ISBN (link)
  7. ↑ Fischer, G.; Aumüller, T. (2003). "Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes". Reviews of Physiology, Biochemistry and Pharmacology. 148: 105–150. doi:10.1007/s10254-003-0011-3. ISBN 978-3-540-40136-0. ISSN 0303-4240. PMID 12698322.{{cite journal}}: CS1 maint: periodical has ISBN (link)
  8. ↑ Prakash, Ajit; Shin, Joon; Rajan, Sreekanth; Yoon, Ho Sup (2016-04-07). "Structural basis of nucleic acid recognition by FK506-binding protein 25 (FKBP25), a nuclear immunophilin". Nucleic Acids Research. 44 (6): 2909–2925. doi:10.1093/nar/gkw001. ISSN 0305-1048. PMC 4824100. PMID 26762975.
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