Targeted Protein Degradation: Principles and Applications of the Proteasome

Abstract

The proteasome is a multi-catalytic protease complex that is involved in protein quality control via three proteolytic activities (i.e., caspase-, trypsin-, and chymotrypsin-like activities). Most cellular proteins are selectively degraded by the proteasome via ubiquitination. Moreover, the ubiquitin–proteasome system is a critical process for maintaining protein homeostasis. Here, we briefly summarize the structure of the proteasome, its regulatory mechanisms, proteins that regulate proteasome activity, and alterations to proteasome activity found in diverse diseases, chemoresistant cells, and cancer stem cells. Finally, we describe potential therapeutic modalities that use the ubiquitin–proteasome system.

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

“…Target protein ligand is the part of the PROTAC molecule that specifically binds to the protein targeted for degradation ( 60 ). The selection of this ligand is critical as it ensures the specificity of the PROTAC for its intended protein target ( 61 ). The PROTAC recruits an E3 ubiquitin ligase, which is responsible for transferring ubiquitin molecules to the target protein, tagging it for degradation.…”

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

“… 49 The ubiquitin–E2 enzyme complex binds to the E3 ubiquitin ligase, which in turn recognizes and binds to the protein to be degraded, catalyzing the transfer of activated ubiquitin from the E2 enzyme to the protein (ubiquitin is covalently bound to lysine residues of target proteins). 50 , 51 This protein, through the addition of several ubiquitin units, is poly‐ubiquitinated, and upon recognition by the 26S proteasome, it is degraded. 52 , 53 Therefore, the UPS is essential for maintaining cellular homeostasis, by eliminating denatured, damaged, mutated, and otherwise unneeded proteins.…”