Identification and comparative analysis of the peptidyl‐prolyl cis/trans isomerase repertoires of H. sapiens, D. melanogaster, C. elegans, S. cerevisiae and Sz. pombe

Abstract

The peptidyl-prolyl cis/trans isomerase (PPIase) class of proteins comprises three member families that are found throughout nature and are present in all the major compartments of the cell. Their numbers appear to be linked to the number of genes in their respective genomes, although we have found the human repertoire to be smaller than expected due to a reduced cyclophilin repertoire. We show here that whilst the members of the cyclophilin family (which are predominantly found in the nucleus and cytoplasm) and the parvulin family (which are predominantly nuclear) are largely conserved between different repertoires, the FKBPs (which are predominantly found in the cytoplasm and endoplasmic reticulum) are not. It therefore appears that the cyclophilins and parvulins have evolved to perform conserved functions, while the FKBPs have evolved to fill ever-changing niches within the constantly evolving organisms. Many orthologous subgroups within the different PPIase families appear to have evolved from a distinct common ancestor, whereas others, such as the mitochondrial cyclophilins, appear to have evolved independently of one another. We have also identified a novel parvulin within Drosophila melanogaster that is unique to the fruit fly, indicating a recent evolutionary emergence. Interestingly, the fission yeast repertoire, which contains no unique cyclophilins and parvulins, shares no PPIases solely with the budding yeast but it does share a majority with the higher eukaryotes in this study, unlike the budding yeast. It therefore appears that, in comparison with Schizosaccharomyces pombe, Saccharomyces cerevisiae is a poor representation of the higher eukaryotes for the study of PPIases.

Osteogenesis Imperfecta

“…The cis-trans isomerization of peptidyl-prolyl bonds that they catalyze is a protein conformational change occurring during protein folding and thought to be rate limiting for type I collagen which contains about 20% proline residues (Gothel and Marahiel, 1999). Unlike most Cyclophilins which are predicted to localize either in the nuclear or cytosolic compartment, Cyclophilin B is localized in the ER (Pemberton and Kay, 2005) or secreted extracellularly (Yao et al, 2005). Because of its interaction with Crtap and P3h1 to form the prolyl 3-hydroxylation complex in the ER, Cyclophilin B became the next logical candidate potentially implicated in recessive forms of OI.…”

An Endoplasmic Reticulum Cyclophilin Cpr5p Rescues Z-type α1-Antitrypsin from Retarded Folding

“…Cyclophilins were originally discovered as cellular targets that bind with high affinity to the immunosuppressive drug cyclosporin A, hCyp40, and hCypNK. 22 After cytosolic hCypA, hCypB is the second most abundant cyclophilin, with an N-terminal signal sequence that targets the protein to the ER, where it localizes mainly in the lumen. 23 An ER stress response element (ERSE), a consensus sequence necessary for transactivation of genes encoding ER chaperones during the unfolded protein response (UPR), is located upstream of the hCypB ORF.…”

“…Saccharomyces cerevisiae has eight different cyclophilins (Cpr1p-Cpr8p), 22 and Cpr5p, a yeast homologue of hCypB, is also localized in the ER.…”

Loss of Secretory Pathway FK506-binding Proteins Results in Cold-sensitive Lethality and Associate Extracellular Matrix Defects in the Nematode Caenorhabditis elegans

“…The FK506-binding proteins (FKBPs or FKBs) 2 belong to a group of proteins that have peptidyl prolyl cis-trans isomerase (PPIase, EC 5.2.1.8) activity, and together with the cyclophilins (CYPs or CYNs) are collectively called the immunophilins. FKBs and CYPs are structurally unrelated and have high affinities for the structurally distinct immunosuppressive drugs FK506 and cyclosporin A, respectively (1).…”

“…The immunophilins have a widespread distribution in nature being found in bacteria, plants, and man. However, the endogenous physiological functions are poorly understood but include possible roles in protein translation, folding, assembly, and trafficking (1,2). These enzymes stabilize the cis-trans transition state, accelerate the isomerization event and therefore promote protein folding and assembly of multiprotein complexes.…”