Peptidylprolyl Cis / Trans Isomerases (Immunophilins): Biological Diversity - Targets - Functions

Abstract

Information recovered from genome sequencing projects, multiple sequence alignments, structural analyses of PPIase and published records were used in deciphering the biological diversity, functions and targets of four groups of proteins encoded by dissimilar sets of sequences whose spatial representations exhibit peptidylprolyl cis/trans isomerase activity (PPIase). In the human genome there are encoded fifteen proteins whose segments have significant homology with the sequence of 12 kDa protein which is the target of the potent immunosuppressive macrolides FK506 or rapamycin. The 12 kDa archetype of the FK506-binding protein (FKBP), known as FKBP-12a, is an abundant intracellular protein whereas other FKBPs possessing from one to four FK506-like binding domains (FKBDs) have nominal masses varying from 13 to 135 kDa. The human genome contains at least sixteen genes encoding proteins comprising one cyclosporin-A (CsA) binding domain (CLD) called cyclophilins whose nominal masses vary from 17 to 324 kDa and multiple coding segments for small cyclophilins (17-19 kDa) whose transcription levels and functions remain unknown. The third group of PPIases encoded in the genome comprises two proteins (hPin1 and hParv14) where hPin1 is an important PPIase for cell cycle. The A. thaliana, C. elegans, D. melanogaster and S. cerevisiae genomes encode a less diverse spectrum of PPIases whereas the prokaryotic genomes contain from none to three cyclophilins, from none to four genes encoding FKBPs, one distant homologue of the Pin1 protein named parvulin and the fourth group of PPIases known as trigger factors. PPIases are discretely distributed to different cellular compartments and interact with a number of targets that control a range of cellular processes. Analyses of the sequence alignments of the two groups of PPIases, namely cyclophilins and FKBPs from diverse phyla, show that in each group their sequences diverge but the amino acid residues which form the PPIase activity site and macrolide binding cavity remain well conserved in the majority of them which suggests that the spatial structures and functions of each group of PPIases remain conserved.

The human FK506-binding proteins: characterization of human FKBP19

“…Only genes where EST-derived sequences are available are included here. Reference to hFKBP-12c (described by Galat, 2003) is omitted from these data since no expressed sequences corresponding to this predicted sequence were found. The FKBP family can be subdivided into four groups by classification of the regions within or surrounding the conserved PPIase domains (figure 1).…”

“…The PPIase families are classified by sequence homology and pharmacologically by their ability to bind the immunosuppressant compounds cyclosporin, FK506 and rapamycin, and are otherwise known as immunophilins (reviewed in Galat andRiviere, 1998, Galat, 2003). The FK506-binding protein (FKBP) family share a high degree of sequence and structural homology and PPIase activity that is specifically inhibited by FK506 or rapamycin (Kay, 1996).…”

“…The FK506-binding protein (FKBP) family share a high degree of sequence and structural homology and PPIase activity that is specifically inhibited by FK506 or rapamycin (Kay, 1996). Since the discovery of the first FKBP (Siekierka et al, 1989), several members of this family have been characterised in humans and other organisms (Patterson et al, 2002, Galat, 2003. Each member of the FKBP family contains one or more PPIase domain, which shows high sequence homology with the most abundant member, FKBP12.…”

Overexpression, purification and assessment of cyclosporin binding of a family of cyclophilins and cyclophilin-like proteins of the human malarial parasite Plasmodium falciparum

“…First, it should be stated that the nomenclature used for this cyclophilin family is similar to the convention reported by Galat [27] in which cyclophilin is abbreviated to CYP and a species-specific prefix, and a suffix representing the approximate molecular mass in kiloDaltons of the mature protein, are added, e.g. PfCYP19A (one of three P. falciparum 19-kDa cyclophilins) [19].…”

“…To our knowledge, the lowest sequence identity to hCYP18 of a known cyclophilin is 7% for a Drosophila melanogaster protein (DmCYP20) [27]. Thus, PfCYP72 was included in this study.…”