PPIases

Peptidyl-prolyl cis-trans isomerases (PPIases) are enzymes that accelerate the cis-trans isomerization of peptide bonds preceding proline residues in proteins. This isomerization can be a rate-limiting step in protein folding and conformational changes, helping proteins attain functional structures more rapidly or adjust their activity in response to cellular signals.

PPIases are classified into three major families. Cyclophilins bind the immunosuppressant cyclosporin A and participate in various cellular processes, including protein folding and signaling. FKBPs (FK506-binding proteins) bind tacrolimus (FK506) and rapamycin and also regulate folding and signaling, with some members interacting with mTOR pathways. Parvulins are a distinct group that includes enzymes like Pin1, which recognizes phosphorylated Ser/Thr-Pro motifs and modulates cell cycle and signaling proteins through isomerization.

These enzymes are found throughout the cell, in the cytosol and various organelles, and often function as part of larger protein complexes. They are sometimes referred to as immunophilins because of their interactions with immunosuppressive drugs, which can disrupt normal PPIase activity and thereby influence immune responses. Beyond folding, PPIases participate in signaling cascades, protein trafficking, and the regulation of transcription factors and other cell-cycle regulators.

Clinically and biologically, PPIases are of interest as therapeutic targets. Inhibitors of cyclophilins and FKBPs are used clinically as immunosuppressants, while dysregulation of PPIase activity has been linked to cancer, neurodegenerative diseases, and viral replication. Ongoing research explores selective modulators to modulate specific PPIase functions with reduced side effects.