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Implications of frequent hitter E3 ligases in targeted protein degradation screens.
Nat Chem Biol
January 2025
Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Targeted protein degradation (TPD) offers a promising approach for chemical probe and drug discovery that uses small molecules or biologics to direct proteins to the cellular machinery for destruction. Among the >600 human E3 ligases, CRBN and VHL have served as workhorses for ubiquitin-proteasome system-dependent TPD. Identification of additional E3 ligases capable of supporting TPD would unlock the full potential of this mechanism for both research and pharmaceutical applications.
View Article and Find Full Text PDF[Exploring protein degradation pathways as therapeutic innovations].
Biol Aujourdhui
January 2025
Université de Caen Normandie, CERMN UR4258, Boulevard Becquerel, 14000 Caen, France.
The disruption of proteostasis provides a favourable context for the emergence of therapeutic innovations, in particular by exploiting technologies such as the PROTAC (Proteolysis Targeting Chimera) approach. These technologies aim to selectively target proteins involved in various diseases, including cancer and neurodegenerative diseases, by inducing their specific degradation via the ubiquitin-proteasome system. The PROTAC approach opens new opportunities for restoring altered protein homeostasis and modulating the pathological consequences of proteostasis deregulation.
View Article and Find Full Text PDFLong-Term Effects of Radiation Therapy on Cerebral Microvessel Proteome: A Six-Month Post-Exposure Analysis.
bioRxiv
January 2025
Abboud Cardiovascular Research Center, Department of Internal Medicine, Carver College of Medicine, University of Iowa.
Background: Radiation therapy (RT) treats primary and metastatic brain tumors, with about one million Americans surviving beyond six months post-treatment. However, up to 90% of survivors experience RT-induced cognitive impairment. Emerging evidence links cognitive decline to RT-induced endothelial dysfunction in brain microvessels, yet studies of endothelial injury remain limited.
View Article and Find Full Text PDFExploration of degrons and their ability to mediate targeted protein degradation.
RSC Med Chem
January 2025
Department of Pharmaceutical Sciences, University of California Irvine California 92617 USA
Degrons are short amino acid sequences that can facilitate the degradation of protein substrates. They can be classified as either ubiquitin-dependent or -independent based on their interactions with the ubiquitin proteasome system (UPS). These amino acid sequences are often found in exposed regions of proteins serving as either a tethering point for an interaction with an E3 ligase or initiating signaling for the direct degradation of the protein.
View Article and Find Full Text PDFVEXAS, Chediak-Higashi syndrome and Danon disease: myeloid cell endo-lysosomal pathway dysfunction as a common denominator?
Cell Mol Biol Lett
January 2025
University Cote d'Azur, Inserm, C3M, Nice, France.
Vacuolization of hematopoietic precursors cells is a common future of several otherwise non-related clinical settings such as VEXAS, Chediak-Higashi syndrome and Danon disease. Although these disorders have a priori nothing to do with one other from a clinical point of view, all share abnormal vacuolization in different cell types including cells of the erythroid/myeloid lineage that is likely the consequence of moderate to drastic dysfunctions in the ubiquitin proteasome system and/or the endo-lysosomal pathway. Indeed, the genes affected in these three diseases UBA1, LYST or LAMP2 are known to be direct or indirect regulators of lysosome trafficking and function and/or of different modes of autophagy.
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