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Molecular Research in Protein Degradation
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Molecular Research in Protein Degradation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 7529

Special Issue Editor

Dr. Daiqing Liao

E-Mail Website
Guest Editor
Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Interests: Chemical biology; cell biology; epigenetics; oncogenic signaling; cell death; cancer metabolism; cancer therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Targeted protein degradation is an essential biological process for maintaining proper cellular homeostasis. Dysregulation of this process is implicated in a range of human diseases, including neurodegenerative diseases and cancer.

Several mechanisms are used for protein degradation. The ubiquitin proteasome system (UPS) is a major and well characterized mechanism of protein degradation. A protein destinated for degradation is recognized by a substrate receptor protein in a specific E3 ubiquitin ligase complex for polyubiquitination and subsequent proteasomal degradation. Proteins can also be degraded through autophagy and other means. In many instances, cell signaling events promote specific posttranslational modifications of proteins, especially phosphorylation, which prime the modified proteins for ubiquitination and degradation. Understanding how a protein is degraded is important not only for our collective knowledge in biology and pathobiology but also for developing means to prevent and treat diseases. Recent advances in utilizing small molecules to achieve targeted protein degradation highlight the importance of fundamental knowledge in biology for developing therapeutics. Conversely, chemical probes and tools have been instrumental to deciphering mechanisms of targeted protein degradation.

This Special Issue of IJMS aims to present a forum of new knowledge dissemination for the protein degradation field. We welcome contributions based on (1) biological studies of protein degradation of specific proteins via a defined mechanism including UPS, autophagy, or other systems, (2) characterization of specific E3 ubiquitin ligases, (3) cell signaling events that specifically regulate protein degradation, and (4) chemical biological studies of protein degradation mediated by small molecules such as molecule glue and heterobifunctional molecules including proteolysis-targeting chimeras (PROTACs).

Dr. Daiqing Liao
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • protein degradation
  • ubiquitin
  • ubiquitination
  • E3 ubiquitin ligase
  • proteasome
  • autophagy
  • cell signaling
  • chemical biology
  • proteolysis-targeting chimeras (PROTACs)
  • molecular glue
  • protein–protein interactions
  • protein posttranslational modifications

Published Papers (5 papers)

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Research

15 pages, 2046 KiB  
Article
mTOR Regulation of N-Myc Downstream Regulated 1 (NDRG1) Phosphorylation in Clear Cell Renal Cell Carcinoma
by Anisha Valluri, Jessica Wellman, Chelsea L. McCallister, Kathleen C. Brown, Logan Lawrence, Rebecca Russell, James Jensen, James Denvir, Monica A. Valentovic, Krista L. Denning and Travis B. Salisbury
Int. J. Mol. Sci. 2023, 24(11), 9364; https://doi.org/10.3390/ijms24119364 - 27 May 2023
Viewed by 1354
Abstract
The mechanistic target of rapamycin (mTOR) kinase is a component of two signaling complexes that are known as mTOR complex 1 (mTORC1) and mTORC2. We sought to identify mTOR-phosphorylated proteins that are differently expressed in clinically resected clear cell renal cell carcinoma (ccRCC) [...] Read more.
The mechanistic target of rapamycin (mTOR) kinase is a component of two signaling complexes that are known as mTOR complex 1 (mTORC1) and mTORC2. We sought to identify mTOR-phosphorylated proteins that are differently expressed in clinically resected clear cell renal cell carcinoma (ccRCC) relative to pair-matched normal renal tissue. Using a proteomic array, we found N-Myc Downstream Regulated 1 (NDRG1) showed the greatest increase (3.3-fold) in phosphorylation (on Thr346) in ccRCC. This was associated with an increase in total NDRG1. RICTOR is a required subunit in mTORC2, and its knockdown decreased total and phospho-NDRG1 (Thr346) but not NDRG1 mRNA. The dual mTORC1/2 inhibitor, Torin 2, significantly reduced (by ~100%) phospho-NDRG1 (Thr346). Rapamycin is a selective mTORC1 inhibitor that had no effect on the levels of total NDRG1 or phospho-NDRG1 (Thr346). The reduction in phospho-NDRG1 (Thr346) due to the inhibition of mTORC2 corresponded with a decrease in the percentage of live cells, which was correlated with an increase in apoptosis. Rapamycin had no effect on ccRCC cell viability. Collectively, these data show that mTORC2 mediates the phosphorylation of NDRG1 (Thr346) in ccRCC. We hypothesize that RICTOR and mTORC2-mediated phosphorylation of NDRG1 (Thr346) promotes the viability of ccRCC cells. Full article
(This article belongs to the Special Issue Molecular Research in Protein Degradation)
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15 pages, 5627 KiB  
Article
Identification of New FG-Repeat Nucleoporins with Amyloid Properties
by Lavrentii G. Danilov, Xenia V. Sukhanova, Tatiana M. Rogoza, Ekaterina Y. Antonova, Nina P. Trubitsina, Galina A. Zhouravleva and Stanislav A. Bondarev
Int. J. Mol. Sci. 2023, 24(10), 8571; https://doi.org/10.3390/ijms24108571 - 10 May 2023
Cited by 2 | Viewed by 1459
Abstract
Amyloids are fibrillar protein aggregates with a cross-β structure. More than two hundred different proteins with amyloid or amyloid-like properties are already known. Functional amyloids with conservative amyloidogenic regions were found in different organisms. Protein aggregation appears to be beneficial for the organism [...] Read more.
Amyloids are fibrillar protein aggregates with a cross-β structure. More than two hundred different proteins with amyloid or amyloid-like properties are already known. Functional amyloids with conservative amyloidogenic regions were found in different organisms. Protein aggregation appears to be beneficial for the organism in these cases. Therefore, this property might be conservative for orthologous proteins. The amyloid aggregates of the CPEB protein were suggested to play an important role in the long-term memory formation in Aplysia californica, Drosophila melanogaster, and Mus musculus. Moreover, the FXR1 protein demonstrates amyloid properties among the Vertebrates. A few nucleoporins (e.g., yeast Nup49, Nup100, Nup116, and human Nup153 and Nup58), are supposed or proved to form amyloid fibrils. In this study, we performed wide-scale bioinformatic analysis of nucleoporins with FG-repeats (phenylalanine–glycine repeats). We demonstrated that most of the barrier nucleoporins possess potential amyloidogenic properties. Furthermore, the aggregation-prone properties of several Nsp1 and Nup100 orthologs in bacteria and yeast cells were analyzed. Only two new nucleoporins, Drosophila melanogaster Nup98 and Schizosaccharomyces pombe Nup98, aggregated in different experiments. At the same time, Taeniopygia guttata Nup58 only formed amyloids in bacterial cells. These results rather contradict the hypothesis about the functional aggregation of nucleoporins. Full article
(This article belongs to the Special Issue Molecular Research in Protein Degradation)
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24 pages, 3006 KiB  
Article
Computational Modeling Analysis of Kinetics of Fumarate Reductase Activity and ROS Production during Reverse Electron Transfer in Mitochondrial Respiratory Complex II
by Nikolay I. Markevich and Lubov N. Markevich
Int. J. Mol. Sci. 2023, 24(9), 8291; https://doi.org/10.3390/ijms24098291 - 05 May 2023
Viewed by 1052
Abstract
Reverse electron transfer in mitochondrial complex II (CII) plays an important role in hypoxia/anoxia, in particular, in ischemia, when the blood supply to an organ is disrupted and oxygen is not available. A computational model of CII was developed in this work to [...] Read more.
Reverse electron transfer in mitochondrial complex II (CII) plays an important role in hypoxia/anoxia, in particular, in ischemia, when the blood supply to an organ is disrupted and oxygen is not available. A computational model of CII was developed in this work to facilitate the quantitative analysis of the kinetics of quinol-fumarate reduction as well as ROS production during reverse electron transfer in CII. The model consists of 20 ordinary differential equations and 7 moiety conservation equations. The parameter values were determined at which the kinetics of electron transfer in CII in both forward and reverse directions would be explained simultaneously. The possibility of the existence of the “tunnel diode” behavior in the reverse electron transfer in CII, where the driving force is QH2, was tested. It was found that any high concentrations of QH2 and fumarate are insufficient for the appearance of a tunnel effect. The results of computer modeling show that the maximum rate of succinate production cannot provide a high concentration of succinate in ischemia. Furthermore, computational modeling results predict a very low rate of ROS production, about 50 pmol/min/mg mitochondrial protein, which is considerably less than 1000 pmol/min/mg protein observed in CII in forward direction. Full article
(This article belongs to the Special Issue Molecular Research in Protein Degradation)
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11 pages, 3750 KiB  
Communication
Shifting the pH Optima of (R)-Selective Transaminases by Protein Engineering
by Chao Xiang, Yu-Fei Ao, Matthias Höhne and Uwe T. Bornscheuer
Int. J. Mol. Sci. 2022, 23(23), 15347; https://doi.org/10.3390/ijms232315347 - 05 Dec 2022
Cited by 10 | Viewed by 1923
Abstract
Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. However, wild-type ATAs usually show pH optima at slightly alkaline values and exhibit low catalytic activity under physiological conditions. For efficient asymmetric synthesis ATAs are commonly used in combination with [...] Read more.
Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. However, wild-type ATAs usually show pH optima at slightly alkaline values and exhibit low catalytic activity under physiological conditions. For efficient asymmetric synthesis ATAs are commonly used in combination with lactate dehydrogenase (LDH, optimal pH: 7.5) and glucose dehydrogenase (GDH, optimal pH: 7.75) to shift the equilibrium towards the synthesis of the target chiral amine and hence their pH optima should fit to each other. Based on a protein structure alignment, variants of (R)-selective transaminases were rationally designed, produced in E. coli, purified and subjected to biochemical characterization. This resulted in the discovery of the variant E49Q of the ATA from Aspergillus fumigatus, for which the pH optimum was successfully shifted from pH 8.5 to 7.5 and this variant furthermore had a two times higher specific activity than the wild-type protein at pH 7.5. A possible mechanism for this shift of the optimal pH is proposed. Asymmetric synthesis of (R)-1-phenylethylamine from acetophenone in combination with LDH and GDH confirmed that the variant E49Q shows superior performance at pH 7.5 compared to the wild-type enzyme. Full article
(This article belongs to the Special Issue Molecular Research in Protein Degradation)
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15 pages, 3284 KiB  
Article
Relationship between Changes in the Protein Folding Pathway and the Process of Amyloid Formation: The Case of Bovine Carbonic Anhydrase II
by Bogdan S. Melnik, Natalya S. Katina, Natalya A. Ryabova, Victor V. Marchenkov, Tatiana N. Melnik, Natalya E. Karuzina and Elena V. Nemtseva
Int. J. Mol. Sci. 2022, 23(23), 14645; https://doi.org/10.3390/ijms232314645 - 24 Nov 2022
Cited by 1 | Viewed by 1253
Abstract
Many proteins form amyloid fibrils only under conditions when the probability of transition from a native (structured, densely packed) to an intermediate (labile, destabilized) state is increased. It implies the assumption that some structural intermediates are more convenient for amyloid formation than the [...] Read more.
Many proteins form amyloid fibrils only under conditions when the probability of transition from a native (structured, densely packed) to an intermediate (labile, destabilized) state is increased. It implies the assumption that some structural intermediates are more convenient for amyloid formation than the others. Hence, if a mutation affects the protein folding pathway, one should expect that this mutation could affect the rate of amyloid formation as well. In the current work, we have compared the effects of amino acid substitutions of bovine carbonic anhydrase II on its unfolding pathway and on its ability to form amyloids at acidic pH and an elevated temperature. Wild-type protein and four mutant forms (L78A, L139A, I208A, and M239A) were studied. We analyzed the change of the protein unfolding pathway by the time-resolved fluorescence technique and the process of amyloid formation by thioflavin T fluorescence assay and electron microscopy. It was revealed that I208A substitution accelerates amyloid formation and affects the structure of the late (molten globule-like)-intermediate state of carbonic anhydrase, whereas the other mutations slow down the growth of amyloids and have either no effect on the unfolding pathway (L78A, L139A) or alter the conformational states arising at the early unfolding stage (M239A). Full article
(This article belongs to the Special Issue Molecular Research in Protein Degradation)
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