Peptidyl Prolylcis/transIsomerases

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.

A staphylococcal cyclophilin carries a single domain and unfolds via the formation of an intermediate that preserves cyclosporin A binding activity

“…Thus, the single domain structure of SaCyp proposed before on the basis of a modeling study data [42] was confirmed by our proteolysis results. However, such single domain structure is not unprecedented as the cyclophilins those have masses nearly similar to that of SaCyp are also shown to carry single domain capable of binding both the substrate and inhibitor [2, 3, 11, 19].…”

“…Cyclophilins, located in the cytosol and membrane or cell organelles, are composed of either single domain or multiple domains [1–3, 19]. The catalytic domains of cyclophilins have a β-barrel conformation that is constituted with eight anti-parallel β-strands, two-three α-helices, and several connecting loops [1, 20, 21].…”