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

Dr. Andrzej Galat
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Guest Editor
Service d’Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, F-91191 Gif/Yvette, France
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
 

Manuscript Submission Information

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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 (10 papers)

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Editorial

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Open AccessEditorial
Introduction to Peptidyl-Prolyl cis/trans Isomerase (PPIase) Series
Biomolecules 2019, 9(2), 74; https://doi.org/10.3390/biom9020074 - 20 Feb 2019
Abstract
About 30 years after the discovery of peptidyl-prolyl cis/trans isomerases (PPIases), research on this group of proteins has become somewhat calmer than it used to be, but it still generates lots of interest [...] Full article

Review

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Open AccessReview
Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52
Biomolecules 2019, 9(2), 52; https://doi.org/10.3390/biom9020052 - 01 Feb 2019
Cited by 2
Abstract
Immunophilins are a family of proteins whose signature domain is the peptidylprolyl-isomerase domain. High molecular weight immunophilins are characterized by the additional presence of tetratricopeptide-repeats (TPR) through which they bind to the 90-kDa heat-shock protein (Hsp90), and via this chaperone, immunophilins contribute to [...] Read more.
Immunophilins are a family of proteins whose signature domain is the peptidylprolyl-isomerase domain. High molecular weight immunophilins are characterized by the additional presence of tetratricopeptide-repeats (TPR) through which they bind to the 90-kDa heat-shock protein (Hsp90), and via this chaperone, immunophilins contribute to the regulation of the biological functions of several client-proteins. Among these Hsp90-binding immunophilins, there are two highly homologous members named FKBP51 and FKBP52 (FK506-binding protein of 51-kDa and 52-kDa, respectively) that were first characterized as components of the Hsp90-based heterocomplex associated to steroid receptors. Afterwards, they emerged as likely contributors to a variety of other hormone-dependent diseases, stress-related pathologies, psychiatric disorders, cancer, and other syndromes characterized by misfolded proteins. The differential biological actions of these immunophilins have been assigned to the structurally similar, but functionally divergent enzymatic domain. Nonetheless, they also require the complementary input of the TPR domain, most likely due to their dependence with the association to Hsp90 as a functional unit. FKBP51 and FKBP52 regulate a variety of biological processes such as steroid receptor action, transcriptional activity, protein conformation, protein trafficking, cell differentiation, apoptosis, cancer progression, telomerase activity, cytoskeleton architecture, etc. In this article we discuss the biology of these events and some mechanistic aspects. Full article
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Open AccessReview
The Many Faces of FKBP51
Biomolecules 2019, 9(1), 35; https://doi.org/10.3390/biom9010035 - 21 Jan 2019
Cited by 3
Abstract
The FK506-binding protein 51 (FKBP51) has emerged as a key regulator of endocrine stress responses in mammals and as a potential therapeutic target for stress-related disorders (depression, post-traumatic stress disorder), metabolic disorders (obesity and diabetes) and chronic pain. Recently, FKBP51 has been implicated [...] Read more.
The FK506-binding protein 51 (FKBP51) has emerged as a key regulator of endocrine stress responses in mammals and as a potential therapeutic target for stress-related disorders (depression, post-traumatic stress disorder), metabolic disorders (obesity and diabetes) and chronic pain. Recently, FKBP51 has been implicated in several cellular pathways and numerous interacting protein partners have been reported. However, no consensus on the underlying molecular mechanisms has yet emerged. Here, we review the protein interaction partners reported for FKBP51, the proposed pathways involved, their relevance to FKBP51’s physiological function(s), the interplay with other FKBPs, and implications for the development of FKBP51-directed drugs. Full article
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Open AccessReview
Versatility of Cyclophilins in Plant Growth and Survival: A Case Study in Arabidopsis
Biomolecules 2019, 9(1), 20; https://doi.org/10.3390/biom9010020 - 10 Jan 2019
Cited by 2
Abstract
Cyclophilins (CYPs) belong to a peptidyl-prolyl cis-trans isomerase family, and were first characterized in mammals as a target of an immunosuppressive drug, cyclosporin A, preventing proinflammatory cytokine production. In Arabidopsis, 29 CYPs and CYP-like proteins are found across all subcellular compartments, involved [...] Read more.
Cyclophilins (CYPs) belong to a peptidyl-prolyl cis-trans isomerase family, and were first characterized in mammals as a target of an immunosuppressive drug, cyclosporin A, preventing proinflammatory cytokine production. In Arabidopsis, 29 CYPs and CYP-like proteins are found across all subcellular compartments, involved in various physiological processes including transcriptional regulation, organogenesis, photosynthetic and hormone signaling pathways, stress adaptation and defense responses. These important but diverse activities of CYPs must be reflected by their versatility as cellular and molecular modulators. However, our current knowledge regarding their mode of actions is still far from complete. This review will briefly revisit recent progresses on the roles and mechanisms of CYPs in Arabidopsis studies, and information gaps within, which help understanding the phenotypic and environmental plasticity of plants. Full article
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Open AccessReview
Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function
Biomolecules 2018, 8(4), 176; https://doi.org/10.3390/biom8040176 - 14 Dec 2018
Cited by 4
Abstract
Cyclophilin D (CyPD) is an important mitochondrial chaperone protein whose mechanism of action remains a mystery. It is well known for regulating mitochondrial function and coupling of the electron transport chain and ATP synthesis by controlling the mitochondrial permeability transition pore (PTP), but [...] Read more.
Cyclophilin D (CyPD) is an important mitochondrial chaperone protein whose mechanism of action remains a mystery. It is well known for regulating mitochondrial function and coupling of the electron transport chain and ATP synthesis by controlling the mitochondrial permeability transition pore (PTP), but more recent evidence suggests that it may regulate electron transport chain activity. Given its identification as a peptidyl-prolyl, cis-trans isomerase (PPIase), CyPD, is thought to be involved in mitochondrial protein folding, but very few reports demonstrate the presence of this activity. By contrast, CyPD may also perform a scaffolding function, as it binds to a number of important proteins in the mitochondrial matrix and inner mitochondrial membrane. From a clinical perspective, inhibiting CyPD to inhibit PTP opening protects against ischemia–reperfusion injury, making modulation of CyPD activity a potentially important therapeutic goal, but the lack of knowledge about the mechanisms of CyPD’s actions remains problematic for such therapies. Thus, the important yet enigmatic nature of CyPD somehow makes it a master regulator, yet a troublemaker, for mitochondrial function. Full article
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Open AccessFeature PaperReview
Structural and Functional Insights into Human Nuclear Cyclophilins
Biomolecules 2018, 8(4), 161; https://doi.org/10.3390/biom8040161 - 04 Dec 2018
Cited by 3
Abstract
The peptidyl prolyl isomerases (PPI) of the cyclophilin type are distributed throughout human cells, including eight found solely in the nucleus. Nuclear cyclophilins are involved in complexes that regulate chromatin modification, transcription, and pre-mRNA splicing. This review collects what is known about the [...] Read more.
The peptidyl prolyl isomerases (PPI) of the cyclophilin type are distributed throughout human cells, including eight found solely in the nucleus. Nuclear cyclophilins are involved in complexes that regulate chromatin modification, transcription, and pre-mRNA splicing. This review collects what is known about the eight human nuclear cyclophilins: peptidyl prolyl isomerase H (PPIH), peptidyl prolyl isomerase E (PPIE), peptidyl prolyl isomerase-like 1 (PPIL1), peptidyl prolyl isomerase-like 2 (PPIL2), peptidyl prolyl isomerase-like 3 (PPIL3), peptidyl prolyl isomerase G (PPIG), spliceosome-associated protein CWC27 homolog (CWC27), and peptidyl prolyl isomerase domain and WD repeat-containing protein 1 (PPWD1). Each “spliceophilin” is evaluated in relation to the spliceosomal complex in which it has been studied, and current work studying the biological roles of these cyclophilins in the nucleus are discussed. The eight human splicing complexes available in the Protein Data Bank (PDB) are analyzed from the viewpoint of the human spliceophilins. Future directions in structural and cellular biology, and the importance of developing spliceophilin-specific inhibitors, are considered. Full article
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Open AccessFeature PaperReview
Dual-Family Peptidylprolyl Isomerases (Immunophilins) of Select Monocellular Organisms
Biomolecules 2018, 8(4), 148; https://doi.org/10.3390/biom8040148 - 15 Nov 2018
Cited by 3
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 [...] Read more.
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 - 31 Oct 2018
Cited by 1
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 [...] Read more.
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 - 11 Oct 2018
Cited by 1
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

Other

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Open AccessTechnical Note
Compression of Large Sets of Sequence Data Reveals Fine Diversification of Functional Profiles in Multigene Families of Proteins: A Study for Peptidyl-Prolyl cis/trans Isomerases (PPIase)
Biomolecules 2019, 9(2), 59; https://doi.org/10.3390/biom9020059 - 11 Feb 2019
Cited by 1
Abstract
In this technical note, we describe analyses of more than 15,000 sequences of FK506-binding proteins (FKBP) and cyclophilins, also known as peptidyl-prolyl cis/trans isomerases (PPIases). We have developed a novel way of displaying relative changes of amino acid (AA)-residues at a given sequence [...] Read more.
In this technical note, we describe analyses of more than 15,000 sequences of FK506-binding proteins (FKBP) and cyclophilins, also known as peptidyl-prolyl cis/trans isomerases (PPIases). We have developed a novel way of displaying relative changes of amino acid (AA)-residues at a given sequence position by using heat-maps. This type of representation allows simultaneous estimation of conservation level in a given sequence position in the entire group of functionally-related paralogues (multigene family of proteins). We have also proposed that at least two FKBPs, namely FKBP36, encoded by the Fkbp6 gene and FKBP51, encoded by the Fkbp5 gene, can form dimers bound via a disulfide bridge in the nucleus. This type of dimer may have some crucial function in the regulation of some nuclear complexes at different stages of the cell cycle. Full article
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