ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation DOI
Cody A. Loy, Eslam M.H. Ali, Laurence J. Seabrook

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

The development of targeted protein degradation by recruiting a interest to ubiquitin ligase facilitate its has become powerful therapeutic tool. potential this approach is limited proteins that can be readily ubiquitinated and relies on having ligand with the various E3 ligases. Here, we describe new methodology for directly recruits proteasome degradation. We generated bifunctional molecules incorporate small molecule into subunit 26S ByeTAC requires binding Rpn-13, nonessential receptor proteasome, does not have rely E cascade ubiquitination. demonstrates application via interactions Rpn-13

Language: Английский

Exploration of Degrons and Their Ability to Mediate Targeted Protein Degradation DOI
Timothy J. Harris, Darci J. Trader

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Degrons are regions of a protein that required to initiate their degradation by cellular machinery.

Language: Английский

Citations

0
Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease DOI Creative Commons
Taylor R. Church, Seth S. Margolis

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 12

Published: Feb. 7, 2025

Neurodegenerative diseases are characterized by the progressive breakdown of neuronal structure and function pathological accumulation misfolded protein aggregates toxic oligomers. A major contributor to deterioration physiology is disruption catabolic pathways mediated proteasome, a large protease complex responsible for most cellular degradation. Previously, it was believed that proteolysis proteasome required tagging targets with polyubiquitin chains, pathway called ubiquitin-proteasome system (UPS). Because this, research on proteasomal roles in neurodegeneration has historically focused UPS. However, additional ubiquitin-independent their importance increasingly recognized. In this review, we discuss range pathways, focusing substrate identification targeting, regulatory molecules adaptors, activators alternative caps, diverse complexes including 20S membrane immunoproteasome, extracellular proteasomes, hybrid proteasomes. These further discussed context aging, oxidative stress, aggregation, age-associated neurodegenerative diseases, special focus Alzheimer's Disease, Huntington's Parkinson's Disease. mechanistic understanding regulation critical development therapies treat these devastating conditions. This review summarizes current state neurodegeneration.

Language: Английский

Citations

0
ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation DOI
Cody A. Loy, Eslam M.H. Ali, Laurence J. Seabrook

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

The development of targeted protein degradation by recruiting a interest to ubiquitin ligase facilitate its has become powerful therapeutic tool. potential this approach is limited proteins that can be readily ubiquitinated and relies on having ligand with the various E3 ligases. Here, we describe new methodology for directly recruits proteasome degradation. We generated bifunctional molecules incorporate small molecule into subunit 26S ByeTAC requires binding Rpn-13, nonessential receptor proteasome, does not have rely E cascade ubiquitination. demonstrates application via interactions Rpn-13

Language: Английский

Citations

0