Special Issue "Evolving Functional Features of Peptidyl-Prolyl cis-trans Isomerases (PPIases) in Mono-Cellular versus Multi-Cellular Organisms"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (30 October 2018)

Special Issue Editor

Guest Editor
Dr. Andrzej Galat

Service d’Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, F-91191 Gif/Yvette, France
E-Mail
Interests: proteomics; bioinformatics; networks of proteins (protein networking) in cells and extracellular matrix

Special Issue Information

More than three decades ago, it was shown that various cells express proteins having peptidyl-prolyl cis-trans isomerase (PPIase) activity, which is one of the essential factors controlling protein folding. Several groups of PPIases are encoded in the genomes of disparate organisms, spanning throughout all kingdoms of life. Multiple genes coding for three distinct families of PPIases have been characterized in those organisms, namely cyclophilins, FKBPs, Pin1 (parvulin in prokaryotes), and trigger factors that are only expressed in prokayotes. Moreover, it was found that mammalian genomes encode fifteen isoforms of the archetypal FKBP12, nineteen different isoforms of cyclophilins, and two isoforms of Pin1. The names of these first two groups of proteins were derived from their capacity to form high-affinity complexes with hydrophobic macrocyclic antibiotics, such as FK506, rapamycin, and cyclosporine A. These three suppressive molecules affect crucial antigen-driven responses of T cells and related networks of cells controlling immune system in mammalian organisms. Since those seminal discoveries, many of the diversified functional features of the PPIases have been investigated; yet many functional and structural aspects of those proteins still wait to be unraveled. Such a diversified set of activities encompassed by various members of the PPIase superfamily of proteins is due to a considerable variation of sequences and structural attributes of the PPIase domains themselves. Large PPIases are fusion proteins containing from one to four consecutive PPIase domains that are flanked by other structural units. Both, small monodomain PPIases and their large forms are involved in diverse activities in the nucleus, i.e., spliceosome assembly and chromatin organization. The large PPIases were originated by splicing of the archetypal PPIase domain (cyclophilin-like and FKBP-like) with various structural units and sequence motifs and the origin of some of them can be traced down to prokaryotes and lower eukaryotes.

Relatively high contents of PPIases in cells suggest that these proteins bind and regulate diverse intracellular signalization networks. For example, it has been shown that some PPIases are associated to supramacromolecular entities and receptors whose functional features can be altered by immunosuppressive and non-immunosuppressive drugs, which have strong affinity to PPIase shallow cavity. Since major changes in signaling networks are due to steric interferences of the effector domain of bound ligand to a given PPIase, it could be suggested that various effector domains of novel natural or synthetic compounds carried by PPIases would modulate various targets in cells. The PPIases are at the interface of protein complexes, RNA– and DNA–protein complexes, and some of them are specifically associated to membrane-embedded proteins and receptors. Decoding diverse physiological effects caused by drugs that use PPIase as intracellular carriers could contribute to the process of selective targeting of those ligands (drugs) and enhancing positive outcomes in clinical treatments of disease.

We, thus, invite scientists working on PPIase research to submit their original research or review articles for publication in this Special Issue. Topics of interest include (but are not restricted to) proteins' networks in which PPIases are involved, functional aspects of PPIases, and biological relevance of immunosuppressive macrolides–PPIase complexes.

Andrzej Galat
Guest Editor
 

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Keywords

  • PPIase
  • Protein folding
  • FKBPs and their targets
  • Cyclophilins
  • Protein networks regulation
  • RNA- and DNA-bound PPIases
  • Clinical aspects of diverse immunosuppressive macrolides–PPIase complexes
  • Selective high affinity binders of PPIases

Published Papers (3 papers)

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Review

Open AccessFeature PaperReview Dual-Family Peptidylprolyl Isomerases (Immunophilins) of Select Monocellular Organisms
Biomolecules 2018, 8(4), 148; https://doi.org/10.3390/biom8040148
Received: 25 October 2018 / Revised: 8 November 2018 / Accepted: 12 November 2018 / Published: 15 November 2018
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Abstract
The dual-family peptidylprolyl cis-trans isomerases (immunophilins) represent a naturally occurring chimera of the classical FK506-binding protein (FKBP) and cyclophilin (CYN), connected by a flexible linker. They are found exclusively in monocellular organisms. The modular builds of these molecules represent two distinct types: CYN-(linker)-FKBP
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The dual-family peptidylprolyl cis-trans isomerases (immunophilins) represent a naturally occurring chimera of the classical FK506-binding protein (FKBP) and cyclophilin (CYN), connected by a flexible linker. They are found exclusively in monocellular organisms. The modular builds of these molecules represent two distinct types: CYN-(linker)-FKBP and FKBP-3TPR (tetratricopeptide repeat)-CYN. Abbreviated respectively as CFBP and FCBP, the two classes also exhibit distinct organism preference, the CFBP being found in prokaryotes, and the FCBP in eukaryotes. This review summarizes the mystery of these unique class of prolyl isomerases, focusing on their host organisms, potential physiological role, and likely routes of evolution. Full article
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Open AccessFeature PaperReview A Functional Analysis of the Cyclophilin Repertoire in the Protozoan Parasite Trypanosoma Cruzi
Biomolecules 2018, 8(4), 132; https://doi.org/10.3390/biom8040132
Received: 3 October 2018 / Revised: 26 October 2018 / Accepted: 29 October 2018 / Published: 31 October 2018
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Abstract
Trypanosoma cruzi is the etiological agent of Chagas disease. It affects eight million people worldwide and can be spread by several routes, such as vectorborne transmission in endemic areas and congenitally, and is also important in non-endemic regions such as the United States
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Trypanosoma cruzi is the etiological agent of Chagas disease. It affects eight million people worldwide and can be spread by several routes, such as vectorborne transmission in endemic areas and congenitally, and is also important in non-endemic regions such as the United States and Europe due to migration from Latin America. Cyclophilins (CyPs) are proteins with enzymatic peptidyl-prolyl isomerase activity (PPIase), essential for protein folding in vivo. Cyclosporin A (CsA) has a high binding affinity for CyPs and inhibits their PPIase activity. CsA has proved to be a parasiticidal drug on some protozoa, including T. cruzi. In this review, we describe the T. cruzi cyclophilin gene family, that comprises 15 paralogues. Among the proteins isolated by CsA-affinity chromatography, we found orthologues of mammalian CyPs. TcCyP19, as the human CyPA, is secreted to the extracellular environment by all parasite stages and could be part of a complex interplay involving the parasite and the host cell. TcCyP22, an orthologue of mitochondrial CyPD, is involved in the regulation of parasite cell death. Our findings on T. cruzi cyclophilins will allow further characterization of these processes, leading to new insights into the biology, the evolution of metabolic pathways, and novel targets for anti-T. cruzi control. Full article
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Open AccessReview The Multiple Roles of Peptidyl Prolyl Isomerases in Brain Cancer
Biomolecules 2018, 8(4), 112; https://doi.org/10.3390/biom8040112
Received: 21 September 2018 / Accepted: 9 October 2018 / Published: 11 October 2018
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Abstract
Peptidyl prolyl isomerases (PPIases) are broadly expressed enzymes that accelerate the cis-trans isomerization of proline peptide bonds. The most extensively studied PPIase family member is protein interacting with never in mitosis A1 (PIN1), which isomerizes phosphorylated serine/threonine–proline bonds. By catalyzing this
[...] Read more.
Peptidyl prolyl isomerases (PPIases) are broadly expressed enzymes that accelerate the cis-trans isomerization of proline peptide bonds. The most extensively studied PPIase family member is protein interacting with never in mitosis A1 (PIN1), which isomerizes phosphorylated serine/threonine–proline bonds. By catalyzing this specific cis-trans isomerization, PIN1 can alter the structure of its target proteins and modulate their activities in a number of different ways. Many proteins are targets of proline-directed phosphorylation and thus PIN1-mediated isomerization of proline bonds represents an important step in the regulation of a variety of cellular mechanisms. Numerous other proteins in addition to PIN1 are endowed with PPIase activity. These include other members of the parvulin family to which PIN1 belongs, such as PIN4, as well as several cyclophilins and FK506-binding proteins. Unlike PIN1, however, these other PPIases do not isomerize phosphorylated serine/threonine–proline bonds and have different substrate specificities. PIN1 and other PPIases are overexpressed in many types of cancer and have been implicated in various oncogenic processes. This review will discuss studies providing evidence for multiple roles of PIN1 and other PPIases in glioblastoma and medulloblastoma, the most frequent adult and pediatric primary brain tumors. Full article
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