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Targeted Protein Degradation
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Targeted Protein Degradation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 4970

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
  • cancer

Published Papers (2 papers)

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Research

16 pages, 2030 KiB  
Article
Modeling of Proteolysis of β-Lactoglobulin and β-Casein by Trypsin with Consideration of Secondary Masking of Intermediate Polypeptides
by Mikhail M. Vorob’ev
Int. J. Mol. Sci. 2022, 23(15), 8089; https://doi.org/10.3390/ijms23158089 - 22 Jul 2022
Cited by 5 | Viewed by 1606
Abstract
The opening of protein substrates during degradation by proteases and the corresponding exposure of their internal peptide bonds for a successful enzymatic attack, the so-called demasking effect, was studied for β-lactoglobulin (β-LG) and β-casein (β-CN) hydrolyzed by trypsin. Demasking was estimated by monitoring [...] Read more.
The opening of protein substrates during degradation by proteases and the corresponding exposure of their internal peptide bonds for a successful enzymatic attack, the so-called demasking effect, was studied for β-lactoglobulin (β-LG) and β-casein (β-CN) hydrolyzed by trypsin. Demasking was estimated by monitoring the redshift in intrinsic tryptophan fluorescence, characterizing the accessibility of polypeptide chains to aqueous medium. The secondary masking of intermediate polypeptides, giving an inverse effect to demasking, caused a restriction of the substrate opening. This led to the limitations in the red shift of fluorescence and the degree of hydrolysis with a long time of hydrolysis of β-LG and β-CN at a constant substrate concentration and reduced trypsin concentrations. The proposed proteolysis model included demasking of initially masked bonds in the protein globule or micelle, secondary masking of intermediate polypeptides, and their subsequent slow demasking. The hydrolysis of peptide bonds was modeled taking into account different hydrolysis rate constants for different peptide bonds. It was demonstrated that demasking competes with secondary masking, which is less noticeable at high trypsin concentrations. Modeling of proteolysis taking into account two demasking processes and secondary masking made it possible to simulate kinetic curves consistent with the experimental data. Full article
(This article belongs to the Special Issue Targeted Protein Degradation)
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17 pages, 3985 KiB  
Article
The Transcription Factor EB (TFEB) Sensitizes the Heart to Chronic Pressure Overload
by Sebastian Wundersitz, Cristina Pablo Tortola, Sibylle Schmidt, Ramon Oliveira Vidal, Melanie Kny, Alexander Hahn, Lukas Zanders, Hugo A. Katus, Sascha Sauer, Christian Butter, Friedrich C. Luft, Oliver J. Müller and Jens Fielitz
Int. J. Mol. Sci. 2022, 23(11), 5943; https://doi.org/10.3390/ijms23115943 - 25 May 2022
Cited by 4 | Viewed by 2715
Abstract
The transcription factor EB (TFEB) promotes protein degradation by the autophagy and lysosomal pathway (ALP) and overexpression of TFEB was suggested for the treatment of ALP-related diseases that often affect the heart. However, TFEB-mediated ALP induction may perturb cardiac stress response. We used [...] Read more.
The transcription factor EB (TFEB) promotes protein degradation by the autophagy and lysosomal pathway (ALP) and overexpression of TFEB was suggested for the treatment of ALP-related diseases that often affect the heart. However, TFEB-mediated ALP induction may perturb cardiac stress response. We used adeno-associated viral vectors type 9 (AAV9) to overexpress TFEB (AAV9-Tfeb) or Luciferase-control (AAV9-Luc) in cardiomyocytes of 12-week-old male mice. Mice were subjected to transverse aortic constriction (TAC, 27G; AAV9-Luc: n = 9; AAV9-Tfeb: n = 14) or sham (AAV9-Luc: n = 9; AAV9-Tfeb: n = 9) surgery for 28 days. Heart morphology, echocardiography, gene expression, and protein levels were monitored. AAV9-Tfeb had no effect on cardiac structure and function in sham animals. TAC resulted in compensated left ventricular hypertrophy in AAV9-Luc mice. AAV9-Tfeb TAC mice showed a reduced LV ejection fraction and increased left ventricular diameters. Morphological, histological, and real-time PCR analyses showed increased heart weights, exaggerated fibrosis, and higher expression of stress markers and remodeling genes in AAV9-Tfeb TAC compared to AAV9-Luc TAC. RNA-sequencing, real-time PCR and Western Blot revealed a stronger ALP activation in the hearts of AAV9-Tfeb TAC mice. Cardiomyocyte-specific TFEB-overexpression promoted ALP gene expression during TAC, which was associated with heart failure. Treatment of ALP-related diseases by overexpression of TFEB warrants careful consideration. Full article
(This article belongs to the Special Issue Targeted Protein Degradation)
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