Proteopedia

Cyclophilin

Function

Cyclophilin (Cyp) binds cyclosporin. They are peptidylprolyl isomerases which catalyze the isomerisation of proline. The Cyp-A/cyclosporin A complex inhibits organ rejection. Cyp-D is a component of the mitochondria permeability pore. Rotamase such as FKBP is a prokaryotic Cyp which is not inhibited by cyclosporin but by FK-506 – an immunosuppressive drug. [1] See also Isomerases.

  • Cyclophilin-A has peptide cis-trans isomerase activity which regulates protein folding and trafficking[2] .
  • Cyclophilin-B interacts with HCV RNA polymerase and stimulates its RNA binding activity[3] .
  • Cyclophilin-C is a component of US2-mediated immune invasion[4] .
  • Cyclophilin-D is a regulator of the mitochondrial permeability transition pore[5] .
  • Cyclophilin-E has a role in osteoblast differentiation by increasing the transcriptional activity of Runx2[6] .
  • Cyclophilin-H mediates interactions between different proteins inside the spliceosome[7] .
  • Cyclophilin-J has upregulated expression in human glioma[8] .
  • Cyclophilin-38 stabilises photosystem II in chloroplasts and supports root growth[9] .
  • Cyclophilin-40 modulates steroid receptor function through its association with Hsp90[10] .

Relevance

Cyp-A has a key role in immunosuppression and viral infection[11]. Cyp-A is the target of the immunosuppressant cyclosporin A whose binding leads to the suppression of the T-cell mediated immune response. Cyp-A is required for effective HIV-1 replication in host cells[12].

Structural highlights

. The acetylation modulates key functions of Cyp-A activity.[13]

3D Structures of Cyclophilin

Cyclophilin 3D structures


Human Cyclophilin-A (rust, olive, turquois, dark green, khaki) complex with cyclosporin A (green, cyan, aqua, neon green, blue) (PDB entry 2x2c)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Stamnes MA, Rutherford SL, Zuker CS. Cyclophilins: a new family of proteins involved in intracellular folding. Trends Cell Biol. 1992 Sep;2(9):272-6. PMID:14731520
  2. ↑ Nigro P, Pompilio G, Capogrossi MC. Cyclophilin A: a key player for human disease. Cell Death Dis. 2013 Oct 31;4(10):e888. PMID:24176846 doi:10.1038/cddis.2013.410
  3. ↑ Watashi K, Ishii N, Hijikata M, Inoue D, Murata T, Miyanari Y, Shimotohno K. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell. 2005 Jul 1;19(1):111-22. PMID:15989969 doi:10.1016/j.molcel.2005.05.014
  4. ↑ Chapman DC, Stocki P, Williams DB. Cyclophilin C Participates in the US2-Mediated Degradation of Major Histocompatibility Complex Class I Molecules. PLoS One. 2015 Dec 21;10(12):e0145458. PMID:26691022 doi:10.1371/journal.pone.0145458
  5. ↑ Amanakis G, Murphy E. Cyclophilin D: An Integrator of Mitochondrial Function. Front Physiol. 2020 Jun 17;11:595. PMID:32625108 doi:10.3389/fphys.2020.00595
  6. ↑ Piao M, Lee SH, Li Y, Choi JK, Yeo CY, Lee KY. Cyclophilin E (CypE) Functions as a Positive Regulator in Osteoblast Differentiation by Regulating the Transcriptional Activity of Runx2. Cells. 2023 Oct 31;12(21):2549. PMID:37947627 doi:10.3390/cells12212549
  7. ↑ Reidt U, Wahl MC, Fasshauer D, Horowitz DS, Luhrmann R, Ficner R. Crystal structure of a complex between human spliceosomal cyclophilin H and a U4/U6 snRNP-60K peptide. J Mol Biol. 2003 Aug 1;331(1):45-56. PMID:12875835
  8. ↑ Chen J, Chen S, Wang J, Zhang M, Gong Z, Wei Y, Li L, Zhang Y, Zhao X, Jiang S, Yu L. Cyclophilin J is a novel peptidyl-prolyl isomerase and target for repressing the growth of hepatocellular carcinoma. PLoS One. 2015 May 28;10(5):e0127668. PMID:26020957 doi:10.1371/journal.pone.0127668
  9. ↑ Duan L, Pérez-Ruiz JM, Cejudo FJ, Dinneny JR. Characterization of CYCLOPHILLIN38 shows that a photosynthesis-derived systemic signal controls lateral root emergence. Plant Physiol. 2021 Mar 15;185(2):503-518. PMID:33721893 doi:10.1093/plphys/kiaa032
  10. ↑ Mark PJ, Ward BK, Kumar P, Lahooti H, Minchin RF, Ratajczak T. Human cyclophilin 40 is a heat shock protein that exhibits altered intracellular localization following heat shock. Cell Stress Chaperones. 2001 Jan;6(1):59-70. PMID:11525244 doi:<0059:hciahs>2.0.co;2 10.1379/1466-1268(2001)006<0059:hciahs>2.0.co;2
  11. ↑ Zhou D, Mei Q, Li J, He H. Cyclophilin A and viral infections. Biochem Biophys Res Commun. 2012 Aug 10;424(4):647-50. doi:, 10.1016/j.bbrc.2012.07.024. Epub 2012 Jul 16. PMID:22814107 doi:http://dx.doi.org/10.1016/j.bbrc.2012.07.024
  12. ↑ Hatziioannou T, Perez-Caballero D, Cowan S, Bieniasz PD. Cyclophilin interactions with incoming human immunodeficiency virus type 1 capsids with opposing effects on infectivity in human cells. J Virol. 2005 Jan;79(1):176-83. PMID:15596813 doi:http://dx.doi.org/10.1128/JVI.79.1.176-183.2005
  13. ↑ Lammers M, Neumann H, Chin JW, James LC. Acetylation regulates cyclophilin A catalysis, immunosuppression and HIV isomerization. Nat Chem Biol. 2010 May;6(5):331-7. Epub 2010 Apr 4. PMID:20364129 doi:10.1038/nchembio.342

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