E3 ubiquitin ligases: structural diversity, dysregulation in disease, and their emerging role in targeted therapeutic strategies

The Ubiquitin-Proteasome System (UPS) is a key mechanism of cellular homeostasis. A central part of this mechanism is E3 ubiquitin ligases, which selectively direct proteins to be ubiquitinated for degradation via the UPS. In this review we give an integrated overview of the classification, structural and the functional characteristics of the main families of E3 ligases, i.e., RING, HECT, RBR and RCR E3 ligases, as well as non-canonical ligase families. Furthermore, we describe how these ligases contribute to several important biological processes like proteostasis, DNA-repair, cell-cycle control, immune-regulation and neurodegeneration. Here we present examples of diseases that occur due to abnormal functioning of E3 ligases (e.g., cancers, neurodegenerative diseases and immune dysfunctions). Finally, the review also covers emerging therapeutic strategies based on E3 ligases with an emphasis on proteolysis-targeting chimeras (PROTACs) and the use of E3 ligase-modulatory approaches to improve CAR-T-cell-based immunotherapies. Recent developments in artificial intelligence and machine learning have already transformed E3-ligase research through the possibility of high-throughput ligand screening, structure-function prediction and rational design of degraders. Our review aims to integrate our knowledge of E3 ligases and show how converging biochemistry, immunotherapy and AI-driven research can lead to novel precision strategies for targeted protein degradation.