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Biomolecules
Special Issues
Transglutaminases: Regulation, Imaging, and Applications
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Transglutaminases: Regulation, Imaging, and Applications

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Enzymology".

Deadline for manuscript submissions: closed (15 July 2024) | Viewed by 3532

Special Issue Editor

Dr. Thomas M. Jeitner

E-Mail Website
Guest Editor
Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA
Interests: transglutaminase 2; protein-glutamine gamma-glutamyltransferase; metabolism; aging; protein structure and function

Special Issue Information

Dear Colleagues,

If form follows function, then transglutaminases are arguably some of the most important enzymes in biology. These enzymes contribute to the formation of the largest and most dynamic structures made by either single-cell or multicellular organisms. For example, transglutaminases crosslink the constituents of the cell walls encasing single cell creatures. Similar reactions result in the formation of the cornified envelope, bones, cartilage, and the extracellular matrix of multicellular organisms. The form of these structures profoundly affects the cells they encompass. And yet, this is just one aspect of the actions catalyzed by this remarkable group of enzymes. In the following Special Issue, we will review the current state-of-art concerning the role of transglutaminases in biological processes and how these might be imaged and regulated.

Dr. Thomas M. Jeitner
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • imaging
  • regulation
  • application
  • clinical translation

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Published Papers (2 papers)

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Research

19 pages, 2387 KiB  
Article
Pharmacological Inhibition of Astrocytic Transglutaminase 2 Facilitates the Expression of a Neurosupportive Astrocyte Reactive Phenotype in Association with Increased Histone Acetylation
by Thomas Delgado, Jacen Emerson, Matthew Hong, Jeffrey W. Keillor and Gail V. W. Johnson
Biomolecules 2024, 14(12), 1594; https://doi.org/10.3390/biom14121594 - 13 Dec 2024
Viewed by 1419
Abstract
Astrocytes play critical roles in supporting structural and metabolic homeostasis in the central nervous system (CNS). CNS injury leads to the development of a range of reactive phenotypes in astrocytes whose molecular determinants are poorly understood. Finding ways to modulate astrocytic injury responses [...] Read more.
Astrocytes play critical roles in supporting structural and metabolic homeostasis in the central nervous system (CNS). CNS injury leads to the development of a range of reactive phenotypes in astrocytes whose molecular determinants are poorly understood. Finding ways to modulate astrocytic injury responses and leverage a pro-recovery phenotype holds promise in treating CNS injury. Recently, it has been demonstrated that ablation of astrocytic transglutaminase 2 (TG2) shifts reactive astrocytes towards a phenotype that improves neuronal injury outcomes both in vitro and in vivo. Additionally, in an in vivo mouse model, pharmacological inhibition of TG2 with the irreversible inhibitor VA4 phenocopied the neurosupportive effects of TG2 deletion in astrocytes. In this study, we extended our comparisons of VA4 treatment and TG2 deletion to provide insights into the mechanisms by which TG2 attenuates neurosupportive astrocytic function after injury. Using a neuron–astrocyte co-culture model, we found that VA4 treatment improves the ability of astrocytes to support neurite outgrowth on an injury-relevant matrix, as we previously showed for astrocytic TG2 deletion. We hypothesize that TG2 mediates its influence on astrocytic phenotype through transcriptional regulation, and our previous RNA sequencing suggests that TG2 is primarily transcriptionally repressive in astrocytes, although it can facilitate both up- and downregulation of gene expression. Therefore, we asked whether VA4 inhibition could alter TG2’s interaction with Zbtb7a, a transcription factor that we previously identified as a functionally relevant TG2 nuclear interactor. We found that VA4 significantly decreased the interaction of TG2 and Zbtb7a. Additionally, we assessed the effect of TG2 deletion and VA4 treatment on transcriptionally permissive histone acetylation and found significantly greater acetylation in both experimental groups. Consistent with these findings, our present proteomic analysis further supports the predominant transcriptionally repressive role of TG2 in astrocytes. Our proteomic data additionally unveiled pronounced changes in lipid and antioxidant metabolism in astrocytes with TG2 deletion or inhibition, which likely contribute to the enhanced neurosupportive function of these astrocytes. Full article
(This article belongs to the Special Issue Transglutaminases: Regulation, Imaging, and Applications)
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14 pages, 2283 KiB  
Article
Conformational Modulation of Tissue Transglutaminase via Active Site Thiol Alkylating Agents: Size Does Not Matter
by Pauline Navals, Alana M. M. Rangaswamy, Petr Kasyanchyk, Maxim V. Berezovski and Jeffrey W. Keillor
Biomolecules 2024, 14(4), 496; https://doi.org/10.3390/biom14040496 - 19 Apr 2024
Cited by 1 | Viewed by 1614
Abstract
TG2 is a unique member of the transglutaminase family as it undergoes a dramatic conformational change, allowing its mutually exclusive function as either a cross-linking enzyme or a G-protein. The enzyme’s dysregulated activity has been implicated in a variety of pathologies (e.g., celiac [...] Read more.
TG2 is a unique member of the transglutaminase family as it undergoes a dramatic conformational change, allowing its mutually exclusive function as either a cross-linking enzyme or a G-protein. The enzyme’s dysregulated activity has been implicated in a variety of pathologies (e.g., celiac disease, fibrosis, cancer), leading to the development of a wide range of inhibitors. Our group has primarily focused on the development of peptidomimetic targeted covalent inhibitors, the nature and size of which were thought to be important features to abolish TG2’s conformational dynamism and ultimately inhibit both its activities. However, we recently demonstrated that the enzyme was unable to bind guanosine triphosphate (GTP) when catalytically inactivated by small molecule inhibitors. In this study, we designed a library of models targeting covalent inhibitors of progressively smaller sizes (15 to 4 atoms in length). We evaluated their ability to inactivate TG2 by measuring their respective kinetic parameters kinact and KI. Their impact on the enzyme’s ability to bind GTP was then evaluated and subsequently correlated to the conformational state of the enzyme, as determined via native PAGE and capillary electrophoresis. All irreversible inhibitors evaluated herein locked TG2 in its open conformation and precluded GTP binding. Therefore, we conclude that steric bulk and structural complexity are not necessary factors to consider when designing TG2 inhibitors to abolish G-protein activity. Full article
(This article belongs to the Special Issue Transglutaminases: Regulation, Imaging, and Applications)
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