Evolving Functional Features of Peptidyl-Prolyl cis-trans Isomerases (PPIases) in Mono-Cellular versus Multi-Cellular Organisms

More than three decades ago, it was shown that various cells express proteins having peptidyl-prolyl cis-trans isomerase (PPIase) activity, which is one of the essential factors controlling protein folding. Several groups of PPIases are encoded in the genomes of disparate organisms, spanning throughout all kingdoms of life. Multiple genes coding for three distinct families of PPIases have been characterized in those organisms, namely cyclophilins, FKBPs, Pin1 (parvulin in prokaryotes), and trigger factors that are only expressed in prokayotes. Moreover, it was found that mammalian genomes encode fifteen isoforms of the archetypal FKBP12, nineteen different isoforms of cyclophilins, and two isoforms of Pin1. The names of these first two groups of proteins were derived from their capacity to form high-affinity complexes with hydrophobic macrocyclic antibiotics, such as FK506, rapamycin, and cyclosporine A. These three suppressive molecules affect crucial antigen-driven responses of T cells and related networks of cells controlling immune system in mammalian organisms. Since those seminal discoveries, many of the diversified functional features of the PPIases have been investigated; yet many functional and structural aspects of those proteins still wait to be unraveled. Such a diversified set of activities encompassed by various members of the PPIase superfamily of proteins is due to a considerable variation of sequences and structural attributes of the PPIase domains themselves. Large PPIases are fusion proteins containing from one to four consecutive PPIase domains that are flanked by other structural units. Both, small monodomain PPIases and their large forms are involved in diverse activities in the nucleus, i.e., spliceosome assembly and chromatin organization. The large PPIases were originated by splicing of the archetypal PPIase domain (cyclophilin-like and FKBP-like) with various structural units and sequence motifs and the origin of some of them can be traced down to prokaryotes and lower eukaryotes.

Relatively high contents of PPIases in cells suggest that these proteins bind and regulate diverse intracellular signalization networks. For example, it has been shown that some PPIases are associated to supramacromolecular entities and receptors whose functional features can be altered by immunosuppressive and non-immunosuppressive drugs, which have strong affinity to PPIase shallow cavity. Since major changes in signaling networks are due to steric interferences of the effector domain of bound ligand to a given PPIase, it could be suggested that various effector domains of novel natural or synthetic compounds carried by PPIases would modulate various targets in cells. The PPIases are at the interface of protein complexes, RNA– and DNA–protein complexes, and some of them are specifically associated to membrane-embedded proteins and receptors. Decoding diverse physiological effects caused by drugs that use PPIase as intracellular carriers could contribute to the process of selective targeting of those ligands (drugs) and enhancing positive outcomes in clinical treatments of disease.

We, thus, invite scientists working on PPIase research to submit their original research or review articles for publication in this Special Issue. Topics of interest include (but are not restricted to) proteins' networks in which PPIases are involved, functional aspects of PPIases, and biological relevance of immunosuppressive macrolides–PPIase complexes.

• PPIase
• Protein folding
• FKBPs and their targets
• Cyclophilins
• Protein networks regulation
• RNA- and DNA-bound PPIases
• Clinical aspects of diverse immunosuppressive macrolides–PPIase complexes
• Selective high affinity binders of PPIases