Peptidyl Prolyl cis/trans Isomerases

Abstract

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.
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Further Reading

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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.

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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.

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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. http://www.els.net [doi: 10.1002/9780470015902.a0003020.pub2]