Peptidyl-prolyl cis/trans isomerases: Introduction

Peptidyl-prolyl isomerases (PPIases) are a superfamily of molecular chaperones, consisting of immunophilins and parvulins, that play widespread roles in protein folding and regulation through isomerization of proline residues [16,18]. The immunophilin family is further subdivided into the FK506-binding proteins (FKBPs) and cyclophilins [10]. The majority of peptide bonds are in trans conformation, due to the steric clashes that occur at the α carbon in the cis orientation [1,3][4,5]. However, proline is different and the cyclized side chain of proline contains both the cis and trans conformations, typically in a ratio of ~20% cis to ~80% trans [5]. Proline isomerization can be the rate limiting step during protein folding and it requires a PPIase to catalyse the cis-trans interconversion [1,5,16]. In addition to protein folding, this unique feature of proline also acts as a regulatory switch in signal transduction. For example, oncogenic p53 is activated after binding of the PPIase Pin1, enhancing malignancy in transformed cells [11,27]. PPIases do not utilize cofactors, such as ATP, to drive their activity; rather, they bind their "clients" using a shallow and promiscuous interface that is thought to favor proline isomerization through conformational selection [20]. Genetic studies have shown that PPIases are essential to the function/folding of proteins important in cancer, neurodegenerative disorders, viral infection, metabolic function and psychiatric disorders [1,9,13,16,22,24]. Although the active site of PPIases is shallow and "undruggable", potent PPIase inhibitors are found in nature, as exemplified by the macrocycles FK506, rapamycin and cyclosporine [5,12]. Intriguingly, some members of the family lack constitutive PPIase activity, indicating additional functions beyond enzyme activity for PPIase domains. Indeed, the inhibitory action of FKBP51 on the nuclear translocation of NF-κB requires the PPIase domain but does not require PPIase enzyme activity [8]. FKBP38 is a mitochondrial protein which contains an inactive PPIase domain, three tetratricopeptide repeat (TPR) domains and a calmodulin binding site. Increases in calcium concentration triggers a conformational change that recruits calmodulin and activates the PPIase activity [7]. Activated FKBP38 can bind to the anti-apoptotic protein Bcl-2 and induce conformation rearrangements that block the interaction between Bcl-2 and the pro apoptotic proteins, such as Bad [7,14,21]. The pro-apoptotic activity of FKBP38 is inhibited by Hsp90 (binds to the TPR domain), which adds a regulatory mechanism to FKBP38 activity [6]. FKBPL is a secreted, divergent member of the FKBP family and it contains a non-functional PPIase domain and three TPR domains [19]. The TPR domains are important for the regulation of steroid hormone receptor signaling and the non-functional PPIase domain is a potent regulator of angiogenesis and cancer stem cell differentiation, through binding to the cell surface receptor CD44 [2,4,15,17,23,25-26].


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