Peptidyl Prolyl cis/trans Isomerases


Peptidyl prolyl cis/trans isomerases (PPIases) are ubiquitous enzymes that catalyse the cis/trans isomerisation of peptide bonds preceding proline in peptides and proteins. PPIases can thus catalyse proline‐limited slow kinetic steps in the folding and rearrangement of proteins. Generally, by the regulation of the biological functions of their target proteins, PPIases are involved in the control of a wide variety of cellular processes, including transcription, cell proliferation, cell differentiation and apoptosis. They are implicated in many diseases such as cancer, inflammation, infection and neurodegeneration. PPIases comprise three families, the cyclophilins, the FK506‐binding proteins (FKBPs) and the parvulins, which are unrelated in their amino acid sequence and their three‐dimensional structure. Binding of cyclophilins and FKBP to their respective tight binding inhibitors, cyclosporin A and FK506, mediates the immunosuppressive action of these drugs by a gain‐of‐function mechanism.

Key Concepts

  • Peptidyl prolyl cis/trans isomerases catalyse the cis/trans isomerisation of peptide bonds preceding proline in peptides and proteins.
  • The enzyme class of PPIases comprises three families, the cyclophilins, the FK506‐binding proteins (FKBPs) and the parvulins unrelated in their amino acid sequence and their three‐dimensional structure.
  • The PPIase activity of members of the cyclophilin family is inhibited by the tight binding inhibitor cyclosporin A.
  • The PPIase activity of members of the FKBP family is inhibited by FK506 and rapamycin.
  • Members of the cyclophilin and FKBP families of PPIases are called immunophilins, because they mediate immunosuppression of the immunosuppressive drugs cyclosporin A, FK506 and rapamycin.
  • Beside a role in protein folding, specific members of the three PPIase families perform specific tasks by the interaction with distinct substrate proteins in their native state, thereby regulating their functional properties.

Keywords: PPIase; cis/trans isomerisation; cyclophilin; FKBP; parvulin; Pin1; cyclosporin A; FK506; immunosuppression; catalysis

Figure 1. Prolyl bond cis/trans isomerisation. In the trans form of the prolyl bond, the two α‐C atoms adjacent to the C–N bond are on opposite sides of the C–N bond which is reflected by the dihedral angle ω of 180°. The cis form of the prolyl bonds is characterised by the two α‐C atoms adjacent to the C–N bond on the same side of the C–N bond which is reflected by the dihedral angle ω of 0°.
Figure 2. The three families of peptidyl prolyl cis/trans isomerases: cyclophilins, FKBPs and parvulins. Comparison of the structures of typical members of the families, numbers of human isoforms, typical inhibitors and human diseases found to be associated with isoforms of the different PPIase families. The crystal structures of the human PPIases CypA (PDB ID: 2CYH), FKBP12 (PDB ID: 1FKB) and Pin1 (PDB ID: 1PIN) are depicted as cartoon representation with the surface of the proteins added in grey. Characteristic residues of the active sites of the PPIases (CypA: Arg55, Gln62, His126; FKBP12: Asp37, Phe99; Pin1: Lys63, Arg68, Arg69) are visualised as orange sticks.


Alanay Y, Avaygan H, Camacho N, et al. (2010) Mutations in the gene encoding the RER protein FKBP65 cause autosomal‐recessive osteogenesis imperfecta. American Journal of Human Genetics 86 (4): 551–559.

Baumann M, Giunta C, Krabichler B, et al. (2012) Mutations in FKBP14 cause a variant of Ehlers‐Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. American Journal of Human Genetics 90 (2): 201–216.

Bell RD, Winkler EA, Singh I, et al. (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485 (7399): 512–516.

Blackburn EA and Walkinshaw MD (2011) Targeting FKBP isoforms with small‐molecule ligands. Current Opinion in Pharmacology 11 (4): 365–371.

Daum S, Lucke C, Wildemann D and Schiene‐Fischer C (2007) On the benefit of bivalency in peptide ligand/pin1 interactions. Journal of Molecular Biology 374 (1): 147–161.

Daum S, Schumann M, Mathea S, et al. (2009) Isoform‐specific inhibition of cyclophilins. Biochemistry 48 (26): 6268–6277.

Dolinski K, Muir S, Cardenas M and Heitman J (1997) All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 94 (24): 13093–13098.

Driver JA, Zhou XZ and Lu KP (2015) Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagen.2014.12.025.

Du H, Guo L, Fang F, et al. (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nature Medicine 14 (10): 1097–1105.

Edlich F, Weiwad M, Erdmann F, et al. (2005) Bcl‐2 regulator FKBP38 is activated by Ca2+/calmodulin. The EMBO Journal 24 (14): 2688–2699.

Edlich F, Weiwad M, Wildemann D, et al. (2006) The specific FKBP38 inhibitor N‐(N',N'‐dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. The Journal of Biological Chemistry 281 (21): 14961–14970.

Erlejman AG, Lagadari M, Harris DC, et al. (2014) Molecular chaperone activity and biological regulatory actions of the TPR‐domain immunophilins FKBP51 and FKBP52. Current Protein & Peptide Science 15 (3): 205–215.

Ernst K, Langer S, Kaiser E, et al. (2014) Cyclophilin‐facilitated membrane translocation as pharmacological target to prevent intoxication of mammalian cells by binary clostridial actin ADP‐ribosylated toxins. Journal of Molecular Biology. DOI: 10.1016/j.jmb.2014.07.013.

Fanghanel J and Fischer G (2004) Insights into the catalytic mechanism of peptidyl prolyl cis/trans isomerases. Frontiers in Bioscience 9: 3453–3478.

Fehr T, Kallen J, Oberer L, et al. (1999) Sanglifehrins A, B, C and D, novel cyclophilin‐binding compounds isolated from Streptomyces sp. A92‐308110. II. Structure elucidation, stereochemistry and physico‐chemical properties. The Journal of Antibiotics 52 (5): 474–479.

Ferbitz L, Maier T, Patzelt H, et al. (2004) Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins. Nature 431 (7008): 590–596.

Fischer G, Bang H and Mech C (1984) Determination of enzymatic catalysis for the cis‐trans‐isomerization of peptide binding in proline‐containing peptides. Biomedica Biochimica Acta 43 (10): 1101–1111.

Fischer G, Gallay P and Hopkins S (2010) Cyclophilin inhibitors for the treatment of HCV infection. Current Opinion in Investigational Drugs 11 (8): 911–918.

Gallay PA (2009) Cyclophilin inhibitors. Clinics in Liver Disease 13 (3): 403–417.

Gerard M, Deleersnijder A, Daniels V, et al. (2010) Inhibition of FK506 binding proteins reduces alpha‐synuclein aggregation and Parkinson's disease‐like pathology. The Journal of Neuroscience 30 (7): 2454–2463.

Halestrap AP (1999) The mitochondrial permeability transition: its molecular mechanism and role in reperfusion injury. Biochemical Society Symposium 66: 181–203.

Hanes SD (2014) Prolyl isomerases in gene transcription. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagen.2014.10.028.

Harrison RK and Stein RL (1990) Substrate specificities of the peptidyl prolyl cis‐trans isomerase activities of cyclophilin and FK‐506 binding protein: evidence for the existence of a family of distinct enzymes. Biochemistry 29 (16): 3813–3816.

Helbig S, Patzer SI, Schiene‐Fischer C, et al. (2011) Activation of colicin M by the FkpA prolyl cis‐trans isomerase/chaperone. The Journal of Biological Chemistry 286 (8): 6280–6290.

Hennig L, Christner C, Kipping M, et al. (1998) Selective inactivation of parvulin‐like peptidyl‐prolyl cis/trans isomerases by juglone. Biochemistry 37 (17): 5953–5960.

Hoffmann H and Schiene‐Fischer C (2014) Functional aspects of extracellular cyclophilins. Biological Chemistry 395 (7–8): 721–735.

Hopkins S and Gallay PA (2014) The role of immunophilins in viral infection. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagen.2014.11.011.

Lee TH, Pastorino L and Lu KP (2011) Peptidyl‐prolyl cis‐trans isomerase Pin1 in ageing, cancer and Alzheimer disease. Expert Reviews in Molecular Medicine 13: e21.

Liu J, Farmer JD Jr Lane WS, et al. (1991) Calcineurin is a common target of cyclophilin‐cyclosporin A and FKBP‐FK506 complexes. Cell 66 (4): 807–815.

Lu Z and Hunter T (2014) Prolyl isomerase Pin1 in cancer. Cell Research 24 (9): 1033–1049.

Malesevic M, Gutknecht D, Prell E, et al. (2013) Anti‐inflammatory effects of extracellular cyclosporins are exclusively mediated by CD147. Journal of Medicinal Chemistry 56 (18): 7302–7311.

Marini JC, Cabral WA, Barnes AM and Chang W (2007) Components of the collagen prolyl 3‐hydroxylation complex are crucial for normal bone development. Cell Cycle 6 (14): 1675–1681.

Nakagawa T, Shimizu S, Watanabe T, et al. (2005) Cyclophilin D‐dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434 (7033): 652–658.

Nigro P, Pompilio G and Capogrossi MC (2013) Cyclophilin A: a key player for human disease. Cell Death & Disease 4: e888.

Rahfeld JU, Rucknagel KP, Schelbert B, et al. (1994) Confirmation of the existence of a third family among peptidyl‐prolyl cis/trans isomerases. Amino acid sequence and recombinant production of parvulin. FEBS Letters 352 (2): 180–184.

Ranganathan R, Lu KP, Hunter T and Noel JP (1997) Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Cell 89 (6): 875–886.

Ratajczak T, Ward BK and Minchin RF (2003) Immunophilin chaperones in steroid receptor signalling. Current Topics in Medicinal Chemistry 3 (12): 1348–1357.

Rycyzyn MA and Clevenger CV (2002) The intranuclear prolactin/cyclophilin B complex as a transcriptional inducer. Proceedings of the National Academy of Sciences of the United States of America 99 (10): 6790–6795.

Schiene‐Fischer C and Yu C (2001) Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases. FEBS Letters 495 (1–2): 1–6.

Schiene‐Fischer C, Aumuller T and Fischer G (2013) Peptide bond cis/trans isomerases: a biocatalysis perspective of conformational dynamics in proteins. Topics in Current Chemistry 328: 35–67.

Siekierka JJ, Hung SH, Poe M, et al. (1989) A cytosolic binding protein for the immunosuppressant FK506 has peptidyl‐prolyl isomerase activity but is distinct from cyclophilin. Nature 341 (6244): 755–757.

Sohocki MM, Bowne SJ, Sullivan LS, et al. (2000) Mutations in a new photoreceptor‐pineal gene on 17p cause Leber congenital amaurosis. Nature Genetics 24 (1): 79–83.

Sokolskaja E and Luban J (2006) Cyclophilin, TRIM5, and innate immunity to HIV‐1. Current Opinion in Microbiology 9 (4): 404–408.

Steinmann B, Bruckner P and Superti‐Furga A (1991) Cyclosporin A slows collagen triple‐helix formation in vivo: indirect evidence for a physiologic role of peptidyl‐prolyl cis‐trans‐isomerase. The Journal of Biological Chemistry 266 (2): 1299–1303.

Stoller G, Rucknagel KP, Nierhaus KH, et al. (1995) A ribosome‐associated peptidyl‐prolyl cis/trans isomerase identified as the trigger factor. The EMBO Journal 14 (20): 4939–4948.

Theuerkorn M, Fischer G and Schiene‐Fischer C (2011) Prolyl cis/trans isomerase signalling pathways in cancer. Current Opinion in Pharmacology 11 (4): 281–287.

Uchida T, Fujimori F, Tradler T, et al. (1999) Identification and characterization of a 14 kDa human protein as a novel parvulin‐like peptidyl prolyl cis/trans isomerase. FEBS Letters 446 (2–3): 278–282.

Unal CM and Steinert M (2014) FKBPs in bacterial infections. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagen.2014.12.018.

Wildemann D, Hernandez Alvarez B, Stoller G, et al. (2007) An essential role for Pin1 in Xenopus laevis embryonic development revealed by specific inhibitors. Biological Chemistry 388 (10): 1103–1111.

Wang XJ and Etzkorn FA (2006) Peptidyl‐prolyl isomerase inhibitors. Biopolymers 84 (2): 125–146.

Further Reading

Bukrinsky M (2014) Extracellular cyclophilins in health and disease. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagen.2014.11.013.

Clevenger CV, Gadd SL and Zheng J (2009) New mechanisms for PRLr action in breast cancer. Trends in Endocrinology and Metabolism 20 (5): 223–229.

Esnault S, Shen ZJ and Malter JS (2008) Pinning down signaling in the immune system: the role of the peptidyl‐prolyl isomerase Pin1 in immune cell function. Critical Reviews in Immunology 28 (1): 45–60.

Fischer G and Wawra S (2006) Polypeptide binding proteins: what remains to be discovered? Molecular Microbiology 61 (6): 1388–1396.

Hanes SD (2014) The Ess1 prolyl isomerase: traffic cop of the RNA polymerase II transcription cycle. Biochimica et Biophysica Acta 1839 (4): 316–333.

Ishikawa Y, Boudko S and Bächinger HP (2015) Ziploc‐ing the structure: triple helix formation is coordinated by rough endoplasmic reticulum resident PPIases. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagen.2014.12.024.

Liou YC, Zhou XZ and Lu KP (2011) Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins. Trends in Biochemical Sciences 36 (10): 501–514.

Satoh K, Shimokawa H and Berk BC (2010) Cyclophilin A: promising new target in cardiovascular therapy. Circulation Journal 74 (11): 2249–2256.

Schiene‐Fischer C (2014) Multidomain peptidyl prolyl cis/trans Isomerases. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagen.2014.11.012.

Seizer P, Gawaz M and May AE (2014) Cyclophilin A and EMMPRIN (CD147) in cardiovascular diseases. Cardiovascular Research 102 (1): 17–23.

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Schiene‐Fischer, Cordelia(May 2015) Peptidyl Prolyl cis/trans Isomerases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003020.pub2]