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: 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
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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  • 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

This special issue is now open for submission, see below for planned papers.

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1) Alina Perrone, Patricia Bustos, Natalia Milduberger and Jacqueline Bua. A functional analysis of the cyclophilin repertoire in the Protozoan parasite Trypanosoma cruzi.

Abstract: Trypanosoma cruzi is the etiological agent of Chagas disease or American Trypanosomiasis, a potential life-threatening illness affecting 7-8 million people. This hemoflagellate protozoan parasite is transmitted by congenital infection, that has become an important epidemiological route of transmission among others. In the last decades, due to increasing migration and travel from Latin America to non-endemic countries, this infection has been detected in the USA, with 300.000 infected people, Europe, with more than 60.000 cases only in Spain, and Western Pacific countries. Our laboratory has been involved in the analysis of the T. cruzi cyclophilin gene family, which comprises 15 paralogues. Five of them are expressed as Peptidyl prolys cis-trans isomerases (PPIase) enzymes. TcCyP19, the parasite 19kDa cyclophilin, was described as an orthologue of human CyPA. This CyP is secreted to the extracellular environment by all parasite stages and is a Cyclosporin A (CsA) - sensitive PPIase. CsA and some CsA non-immunosuppressive analogs have shown in vitro and in vivo anti-parasitic activity. The CsA analogs that had the best performance as trypanocidal drugs were those that showed correlation with the total potential complex energy of these compounds with the TcCyP19 cyclophilin like domain, analysed by three-dimensional molecular modelling studies. The extracellular secretion of this cyclophilin lead us to analyse a possible role in the the host - parasite interactions. CsA also proved to inhibit parasite cell death events caused by oxidative stress, as cytochrome c translocation to cytosol, DNA degradation and significantly diminished mitochondrial membrane potential, implying an inhibition of the “mitochondrial permeability transition pore-like” opening. With this finding, we described this process in a protozoan parasite for the first time. We further investigated if a T. cruzi cyclophilin was involved in these cell death events, and found that the mitochondrial TcCyP22, which is an orthologue of the mammalian CyPD, was involved. Another T. cruzi cyclophilin of 21 kDa was localized to endoplasmic reticulum and could be involved in calcium transport. Finally, we aimed to study the course of this parasitic infection in cells and mice deficient for the mammalian mitochondrial peptidyl-prolyl cis-trans isomerase F gene, (Ppif-/- or CyPD), and preliminary histopathological analysis and immunological studies showed significant differences between T. cruzi infected Ppif-/- and wild type mice. Further experiments will help to unravel role of CyPD and the mitochondrial permeability transition in the in vitro and in vivo T. cruzi infection. Our findings on T. cruzi cyclophilins will allow the further characterization of the pathways involving cell death and host-parasite interactions in trypanosomes that will lead to important insights into the biology of these parasites, the evolution of metabolic pathways, and ultimately novel targets for anti-parasitic intervention.

2) Andrzej Galat. Compression of large sets of sequence data reveals fine diversification of functional profiles in multigene families of proteins: a study case for Peptidyl-Prolyl cis/trans Isomerases (PPIase).

Abstract: Large-size sets of sequences of three major families of peptidyl-prolyl cis/trans isomerases (PPIases) were analyzed with a novel library of algorithms. For example, analyses of about 5000 sequences of cyclophilins, which are orthologues to their eighteen human counterparts, have revealed that those groups display largely diversified sequence-structure-function dependent profiles. It is proposed that coupling of such analyses with experimentally-derived proteomics data on PPIases may contribute to a better understanding of their fine interaction patterns with various intracellular targets that might be controlled by small natural molecular mass inhibitors. Such analyses could be useful for betterment of pharmacological applications of small inhibitors of PPIase in diverse medical applications.

3) Andreas Hähle, Stephanie Merz, Christian Meyners, Felix Hausch. The many mechanistic faces of FKBP51.

4) Sailen Barik. Dual-Family Peptidylprolyl Isomerases (Immunophilins) of Select Monocellular Organisms.

Abstract: The dual-family peptidylprolyl cis-trans isomerases (immunophilins) represent naturally occurring chimera of classical FK506-binding protein (FKBP) and cyclophilin (CYN), connected by a flexible linker, and are found exclusively in monocellular organisms. The modular builds of these molecules represent two distinct types: CYN-(linker)-FKBP and FKBP-3TPR-CYN. Abbreviated respectively as CFBP and FCBP, the two classes also exhibit distinct organism preference, the CFBP being found in prokaryotes, and 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.

5) Caroline Rajiv and Tara L. Davis. Structural and Functional Insights into Human Nuclear Cyclophilins.

1. Introduction: the place of nuclear cyclophilins within the family

1.1. Short intro to the cyclophilin family

1.1.1. Description, evolution, known biology

1.2. Nuclear cyclophilins

1.2.1. Biochemical/structural characterization of this unique sub-set of family members: Domain architectures, sequence conservation in active site, substrate/inhibitor specificities

1.2.2. Participation in nuclear processes, general overvie: The Aquarius complex (DNA repair), chromatin remodeling (PPIE:MLL:HDAC1), regulation of transcription, presence in spliceosomes

2. What is known about each of the nuclear cyclophilins?

Each of the eight human nuclear cyclophilins (PPIE, PPIG, PPIH, PPIL1, PPIL2, PPIL3, PPWD1 and CWC27) will be characterized, including: a description of their domain architecture and a summary of what is known concerning peptidyl-prolyl isomerase activity and high-resolution structure; a review of structural information and protein–protein interactions within the spliceosome; and, when applicable, an evaluation of the literature concerning other nuclear functions for each nuclear cyclophilin. 

 3. Future questions

3.1. Structural Biology: how to define interesting protein–protein interactions, and how to interpret interactions within macromolecular structures vs. study of smaller complexes

3.1.1. Orthosteric interactions vs. allosteric ones

3.1.2. Do smaller studies complement or contradict data from larger complexes?

3.2. Biology: how to summarize the roles cyclophilins play in the nucleus, and how to study them?

3.2.1. Specific vs. non-specific or cross-specific effects

3.2.2. The role of cyclophilins in interactions with disordered regions/proteins of the spliceosome

3.2.3. Significance of “moonlighting” cyclophilins: Proline-dependent vs. proline-independent effects in the nucleus, how intron retention may tie altered splicing to transcriptional regulation—or how other mechanisms, some more direct, may be responsible

3.3. Pharmacology: how to design isoform-selective inhibitors to study roles in cell?

3.3.1. Importance of specific inhibitors (or at least specificity in cellular compartments) to dissecting cellular function

3.3.2. Parallels between the pro’s and con’s of inhibiting the spliceosome and those of inhibiting the cyclophilins; what strategies may be more efficient/specific?

6) Nadia R. Zgajnar, Sonia A. De Leo, Cecilia M. Lotufo, Alejandra G. Erlejman and Mario D. Galigniana. Molecular mechanisms underlying the biological actions of Hsp90-binding immunophilins.

Abstract: The structure of low molecular weight immunophilins related to immunosuppression only show the FK1 domain, which is the signature domain of a family of proteins that shows peptidyprolyl isomerase enzymatic activity. In contrast, the so-called high molecular weight immunophilins such as the Hsp90-binding immunophilin subfamily are characterized by the additional presence of TPR domains, through which they bind to the 90-kDa heat-shock protein, Hsp90. Via this molecular chaperone, Hsp90-binding immunophilins can interact and regulate the biological function of a great number of client proteins. These immunophilins were first described as members of the oligomeric Hsp90/Hsp70-based heterocomplex bound to steroid receptors affecting their biological actions. Afterwards, they emerged as likely contributors to a variety of other hormone-dependent diseases, stress-related pathologies, immune and reproductive physiology, cancers, psychiatric disorders, Alzheimer’s disease and several other protein aggregate disorders. Many biological actions of these immunophilins have been assigned to the structurally similar, but functionally divergent FK1 domain and the close proline-rich loop sequence suspended above the isomerase pocket. Nonetheless, immunophilins also require the complementary input of the TPR domain, most likely due to their dependence with the association to Hsp90 as a functional unit. High molecular weight immunophilins regulate a variety of biological processes such as transcriptional activity, cell proliferation, telomerase activity, apoptosis, cancer progression, metastasis, angiogenesis, cytoskeleton architecture, neurodifferentiation, neuroregeneration, etc. In this review article we discuss the biology of these events and their mechanistic aspects.

7) George Porter et al. Cyclophilin D master regulator or trouble maker of mitochondrial function.

Abstract: Cyclophilin D (CyPD), the product of the PPIF gene, is a peptidyl-prolyl, cis-trans isomerase residing in the mitochondrial matrix, but the exact mechanisms by which CyPD is regulates and is regulated by mitochondrial function remain enigmatic. Traditionally, CyPD has been thought to regulate the opening of mitochondrial permeability transition pore (PTP), a large conductance pore whose opening depolarizes the mitochondrial inner membrane to decrease ATP production and increase reactive oxygen species production, which causes cellular necrosis if this opening is sustained. The presence of a number of CyPD-binding partners in the mitochondrial inner membrane and matrix, such as the adenine nucleotide translocator (ANT), the phosphate carrier (PiC), and the oligomycin sensitivity conferral protein (OSCP), support the idea that CyPD controls the creation of the PTP from the ATP synthase (complex V of the electron transport chain). However, it remains unclear how CyPD’s PPIase activity is involved in this process because targets of this activity have not been reported. Recent evidence suggests that the interaction of CyPD with other proteins may also be important for regulating mitochondrial function. In addition, data suggests that CyPD plays a role in the assembly of the electron transport chain, making CyPD a central node for control of mitochondrial function.

1. Introduction to mitochondrial ETC function, the PTP, and the idea that the PTP is regulated by CyPD.

2. Evolution of CyPD (don’t know anything about this—perhaps Kambiz has something on this.

3. CyPD regulates the PTP

3.1. Inhibition by cyclosporins.

3.2. Physiologic regulation of CyPD

4. CyPD regulates mitochondrial function

5. CyPD enzymatic targets: data, or lack thereof

6. CyPD binding partners

7. Model of CyPD’s regulation of mitochondrial function

8) Izailda Barbosa Dos Santos and Sang Wook Park. Role of PPlase during innate immunity.

Outline: We will cover PPlases that are involved in plant innate immunity. We will starting with discussing their roles and functions throughout various stages of plant immune responses, and correlate them with similar roles and mechanisms in other organisms. In line with this scenario, we will emphasize their roles in plant defense hormone signaling, and their cross talk with growth and development (energy tradeoffs).

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