Abstract
The dual-family peptidylprolyl cis-trans isomerases (immunophilins) represent a naturally occurring chimera of the classical FK506-binding protein (FKBP) and cyclophilin (CYN), connected by a flexible linker. They are found exclusively in monocellular organisms. The modular builds of these molecules represent two distinct types: CYN-(linker)-FKBP and FKBP-3TPR (tetratricopeptide repeat)-CYN. Abbreviated respectively as CFBP and FCBP, the two classes also exhibit distinct organism preference, the CFBP being found in prokaryotes, and the FCBP in eukaryotes. This review summarizes the mystery of these unique class of prolyl isomerases, focusing on their host organisms, potential physiological role, and likely routes of evolution.
Highlights
To start with, a quick note on nomenclature used in this review is in order
The terms “immunophilin” and “peptidylprolyl cis-trans isomerase” (PPI or PPIase) have often been used interchangeably, since both are rooted in the early discovery that these proteins bind the immunosuppressive drugs cyclosporin and FK506, respectively, and catalyze cis-trans isomerization of the peptidylprolyl bonds in proteins [4,5,6]
FK506-FK506-binding protein (FKBP) complexes, in spite of the highly dissimilar sequences of CYN and FKBP, bind to and inhibit calcineurin; this reduces the dephosphorylation of NF-AT, a calcineurin substrate and a transcription factor [7,8]
Summary
The two classic immunophilin families are cyclophilin and the FK506-binding protein, traditionally abbreviated as CYP and FKBP, respectively [1,2]. Though the binding generally leads to inhibition of the PPIase activity, the immunosuppressive function of these drugs is due to the ability of the drug-PPI complexes to inhibit key signaling proteins. Both CsA-CYN and FK506-FKBP complexes, in spite of the highly dissimilar sequences of CYN and FKBP, bind to and inhibit calcineurin (a Ca+2 -dependent protein phosphatase); this reduces the dephosphorylation of NF-AT (nuclear factor of activated T-cells), a calcineurin substrate and a transcription factor [7,8]. Can be found elsewhere [17,18,19]
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