Cyclophilin

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[[Image:2x25.jpg|left|200px|thumb|Crystal Structure of human Cyclophilin-A, [[2x25]]]]
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<StructureSection load='2x2c' size='350' side='right' caption='Human Cyclophilin-A (rust, olive, turquois, dark green, khaki) complex with cyclosporin A (green, cyan, aqua, neon green, blue) (PDB entry [[2x2c]])' scene='41/415818/Cv/1'>
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{{STRUCTURE_2x25| PDB=2x25 | SIZE=300| SCENE= |right|CAPTION=human Cyclophilin-A, [[2x25]] }}
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== Function ==
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[[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. The images at the left and at the right correspond to one representative Cyclophilin, ''i.e.'' crystal structure of human Cyclophilin A ([[2x25]]).
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[[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. <ref>PMID:14731520</ref> See also [[Isomerases]].
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*'''Cyclophilin-A''' has peptide cis-trans isomerase activity which regulates protein folding and trafficking<ref>PMID:24176846</ref> .
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*'''Cyclophilin-B''' interacts with HCV RNA polymerase and stimulates its RNA binding activity<ref>PMID:15989969</ref> .
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*'''Cyclophilin-C''' is a component of US2-mediated immune invasion<ref>PMID:26691022</ref> .
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*'''Cyclophilin-D''' is a regulator of the mitochondrial permeability transition pore<ref>PMID:32625108</ref> .
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*'''Cyclophilin-E''' has a role in osteoblast differentiation by increasing the transcriptional activity of Runx2<ref>PMID:37947627</ref> .
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*'''Cyclophilin-H''' mediates interactions between different proteins inside the spliceosome<ref>PMID:12875835</ref> .
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*'''Cyclophilin-J''' has upregulated expression in human glioma<ref>PMID:26020957</ref> .
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*'''Cyclophilin-38''' stabilises photosystem II in chloroplasts and supports root growth<ref>PMID:33721893</ref> .
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*'''Cyclophilin-40''' modulates steroid receptor function through its association with Hsp90<ref>PMID:11525244</ref> .
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{{TOC limit|limit=2}}
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== Relevance ==
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== 3D Structures of Cyclophilin ==
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Cyp-A has a key role in immunosuppression and viral infection<ref>PMID:22814107</ref>. 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<ref>PMID:15596813</ref>.
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== Structural highlights ==
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=== Cyclophilin-A ===
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<scene name='41/415818/Cv/2'>Cyp-A undergoes post-translational acetylation of Lys125</scene>. The acetylation modulates key functions of Cyp-A activity.<ref>PMID:20364129</ref>
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== 3D Structures of Cyclophilin ==
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[[Cyclophilin 3D structures]]
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[[2x25]], [[2x2a]], [[3k0m]], [[3k0n]], [[1w8l]], [[1w8m]], [[1w8v]], [[1rmh]], [[2cpl]] – hCyp-A – human
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</StructureSection>
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[[1oca]] – hCyp-A - NMR<br />
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[[3k0o]], [[3k0p]], [[3k0q]], [[3k0r]], [[2alf]] – hCyp-A (mutant)<br />
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[[2a2c]], [[1cwa]], [[1cwb]], [[1cwc]] – hCyp-A+cyclosporin A<br />
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[[3cys]] - hCyp-A+cyclosporin A - NMR<br />
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[[1cwj]], [[1bck]], [[1cwi]], [[1cwo]], [[1cwf]], [[1cwh]], [[1cwk]], [[1cwl]], [[1cwm]], [[1mik]] - hCyp-A+cyclosporin A derivative<br />
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[[2rma]], [[2rmb]] - hCyp-A+cyclosporin A+cyclosporin A derivative<br />
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[[1mf8]], [[1m63]] - hCyp-A+cyclosporin A+ calcineurin subunits A,B<br />
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[[2x2d]], [[1m9c]], [[1m9d]], [[1m9e]], [[1m9f]], [[1m9x]], [[1m9y]], [[1awq]], [[1awr]], [[1aws]], [[1awt]], [[1awu]], [[1awv]], [[1ak4]], [[1fgl]] - hCyp-A+HIV-1 N-terminal capsid domain<br />
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[[1zkf]] – hCyp-A+suc-AGPF-pNA<br />
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[[1ynd]], [[1nmk]] – hCyp-A+ sanglifehrin<br />
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[[2cyh]], [[3cyh]], [[4cyh]], [[5cyh]] - hCyp-A+dipeptide<br />
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[[1vbs]], [[1vbt]] – hCyp-A+tetrapeptide<br />
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[[1vdn]] – yCyp-A+peptidyl coumarin – yeast<br />
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[[1ist]] – yCyp-A<br />
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[[1w74]] – Cyp-A – ''Mycobacterium tuberculosis''<br />
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[[1lop]] - EcCyp-A+peptidyl nitroanilide - ''Escherichia coli''<br />
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[[1csa]] – EcCyp-A+ cyclosporin A – NMR<br />
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=== Cyclophilin-B ===
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[[3ich]] – hCyp-B<br />
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[[3ici]] - hCyp-B+calmegin fragment<br />
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[[1v9t]] – EcCyp-B+peptidyl nitroanilide <br />
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[[1vai]] - EcCyp-B+peptidyl coumarin<br />
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[[1cyn]] – hCyp-B +cyclosporin A derivative<br />
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[[1j2a]] – EcCyp-B (mutant)<br />
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=== Cyclophilin-C ===
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[[2esl]] - hCyp-C+cyclosporin A<br />
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[[2rmc]] - Cyp-C+cyclosporin A – mouse<br />
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=== Cyclophilin-D ===
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[[2bit]] – hCyp-D<br />
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[[2viu]] – hCyp-D+DMSO<br />
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[[2z6w]] - hCyp-D+cyclosporin A<br />
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=== Cyclophilin-E ===
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[[2kyx]], [[1zmf]] – hCyp-E PPIASE domain<br />
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[[2r99]] - hCyp-E ABH-like domain<br />
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[[2cqb]] – hCyp-E RNA recognition motif<br />
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[[2ck1]], [[2cmt]] – Cyp-E – ''Schistosoma mansoni''<br />
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[[2kyx]] – hCyp-E RRM domain – NMR<br />
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[[3lpy]], [[3mdf]] - hCyp-E RRM domain<br />
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=== Cyclophilin-G ===
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[[2wfi]], [[2gw2]] - hCyp-G PPIASE domain<br />
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[[2wfj]] - hCyp-G PPIASE domain+cyclosporin A<br />
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=== Cyclophilin-H ===
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[[1mzw]] – hCyp-H+peptide<br />
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=== Cyclophilin-J ===
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[[2ok3]], [[1xyh]] - hCyp-J<br />
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[[2oju]] - hCyp-J+cyclosporin A<br />
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=== Cyclophilin-3 ===
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[[2igv]], [[2igw]], [[1e8k]] – CeCyp-3+dipeptide – ''Caenorhabditis elegans''<br />
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[[1dyw]] - CeCyp-3<br />
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[[1e3b]] – CeCyp-3+AUP(ET)3<br />
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=== Cyclophilin-5 ===
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[[1h0p]] – CeCyp-5 (mutant) <br />
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Cyclophilin-40
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[[1ihg]], [[1iip]] – Cyp-40 – bovine<br />
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=== Cyclophilin ===
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[[3bo7]] - TgCyp+cyclosporin A - ''Toxoplasma gondii''<br />
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[[2nul]] – EcCyp<br />
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[[1clh]] – EcCyp – NMR<br />
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[[1qoi]] – hCyp SNUCYP-20<br />
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[[3k2c]] – Cyp – ''Encephalitozoon cuniculi''<br />
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[[3eov]] - LdCyp+cyclosporin A – ''Leishmania donovani''<br />
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[[3bt8]] – LdCyp<br />
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[[2haq]] – LdCyp-A<br />
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[[2hqj]] – Cyp – ''Leishmania major''<br />
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[[3bkp]] – TgCyp<br />
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[[2cfe]] – Cyp – ''Malassezia sympodialis''<br />
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[[2c3b]] – Cyp – ''Aspergillus fumigatus''<br />
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[[1z81]] – Cyp – ''Plasmodium Yoelli''<br />
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[[1qng]] – PfCyp+cyclosporin A – ''Plasmodium falciparum''<br />
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[[1qnh]] – PfCyp (mutant)+cyclosporin A<br />
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[[1xo7]] – TcCyp – ''Trypanosoma cruzi''<br />
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[[1xq7]] - TcCyp+cyclosporin A<br />
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[[1a58]] - Cyp – ''Brugia malayi''<br />
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[[2ko7]] – BpCyp+inhibitor – ''Burkholderia pseudomallei''<br />
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[[2ke0]] – BpCyp – NMR
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=== Rotamase (FKBP) ===
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[[1fks]], [[1fkt]], [[1fkr]], [[2kfw]] – EcFKBP – NMR<br />
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== References ==
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[[1q6h]], [[1q6u]] – EcFKBP<br />
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<references/>
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[[1q6i]] – EcFKBP+FK-506<br />
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[[Category:Topic Page]]
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[[3jxv]], [[3jym]] – FKBP73 – wheat<br />
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[[3mdy]] – hFKBP-1A+BMPR1B<br />
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[[3h9r]] - hFKBP-1A+ activin receptor type I<br />
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[[1j4r]] – hFKBP-1+FKB-001<br />
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[[2ppp]], [[2ppn]], [[2dg3]], [[1d6o]] – hFKBP-12<br />
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[[2ppo]] – hFKBP-12 (mutant)<br />
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[[2dg4]], [[1fkb]] - hFKBP-12+rapamycin<br />
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[[2fap]], [[1nsg]], [[1fap]] - hFKBP-12+rapamycin+FRB<br />
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[[1f40]] - hFKBP-12+GPI-1046<br />
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[[1a7x]] – hFKBP-12+FK-1012<br />
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[[1d7h]], [[1d7i]], [[1d7j]], [[1fkg]], [[1fkh]], [[1fki]] - hFKBP-12+ligand<br />
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[[2dg9]] - hFKBP-12 (mutant)+rapamycin<br />
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[[1fkl]] - cFKBP-12+rapamycin - cow<br />
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[[2pbc]] - hFKBP-13<br />
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[[1y0o]], [[1u79]] – AtFKBP-13 - ''Arabidopsis thaliana''<br />
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[[2kfv]] – hFKBP-25 N-terminal<br />
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[[2vn1]] – PfFKBP-35 FK506-binding domain+FK506<br />
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[[3b7x]] – hFKBP-36 <br />
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[[2if4]] – AtFKBP<br />
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[[2f4e]] - AtFKBP-42 N-terminal<br />
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[[1kt0]], [[1kt1]] – hFKBP-51 (mutant)<br />
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[[1ix5]] – FKBP – ''Methanothermococcus thermolithotrophicus'' – NMR<br />
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[[1bl4]] – hFKBP (mutant)+inhibitor<br />
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[[1bkf]] – hFKBP (mutant)+FK-506<br />
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[[1fkf]] - hFKBP+FK-506<br />
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[[1fkr]], [[1fks]], [[1fkt]] – hFKBP - NMR<br />
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Current revision

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

References

  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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