PPIase

A cytosolic binding protein for CsA was first isolated in 1984 and named cyclophilin, later cyclophilin A (CyPA), in reference to its high affinity for CsA (18). CyPA is a basic, abundant protein with a mass of 18 kDa, and it is found in a variety of tissues. The first clue to its function came in 1989 when two independent groups isolated the enzyme that catalyzes pepti-dyl proline isomerization/peptidylprolyl cis-trans isomerase (EC 5.2.1.8 PPIase), in protein chains and (re)discovered CyPA (19, 20). CyPA is a potent PPIase, and its enzymatic activity is strongly inhibited by CsA. 

Fluorine in biological mimics Peptidyl prolyl isomerases (PPIases)... 

Protein family PDI Cyclophilin PPIase FKBP PPIase Hsp60 Hsp70 Hsp90... 

Cytosol Thioredoxin PPIase b GroEL DnaK HtpG (C62.5)... 

Peptidyl prolyl cis-trans isomerases (PPIases) are able to catalyze the folding or unfolding reaction. 

The third family of PPIases, the parvulins, does not belong to immunophilins because family members do not show affinity to immunosuppressive drugs. In all cases the prototypic family members are small, single-domain proteins expressed in high abundance predominantly in the cytosol of mammalian and bacterial cells. 

To form catalytically productive enzyme/substrate complexes, many peptide bond cis-trans isomerases essentially require the location of the reactive bond of the substrate in the context of secondary binding sites or a specific spatial organization of the polypeptide chain thus creating features of stereo- and regiospecifi-city [19,20]. As in the case of many endoproteases, PPIases can utilize an extended array of catalytic subsites to enhance catalytic efficiency and substrate specificity. These properties precondition peptide bond cis-trans isomerases toward a complex reaction pattern. Consequently, biochemical investigations have led to the elucidation of three distinct molecular mechanisms that might be operative either in isolation or collectively in the cellular action of both prototypical and multidomain peptide bond cis-trans isomerases ... 

Several studies have highlighted the importance of multidomain FKBPs in the control of signal transduction pathways. For example, hFKBP51 and hFKBP52 have been found in steroid hormone receptor complexes and are thought to play an important role in complex formation and translocation of receptor-ligand complexes from the cytosol into the nucleus [82,83], Notably, these multidomain FKBPs share structural characteristics as demonstrated by an N-terminal PPIase... 

Identification of signaling pathways solely affected by inhibition of the PPIase activity is critical for obtaining a complete picture of cellular responses mediated by FKBP-sensitive prolyl isomerizations. 

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