Ubiquitin E3 ligases are directly implicated in cancer, neurodegeneration, and immune-related diseases. A detailed understanding of their molecular and structural mechanisms is essential for advancing therapeutic strategies.
Using an integrated chemical biology, biochemical, and structural approach, we have substantially expanded the known landscape of E3 ligase subtypes. Notably, we have identified and characterized novel classes—including Ring-Cys-Relay (RCR), hemiRING, and RNF213/ZNFX1 (RZ)—that play critical roles in axonal integrity, cancer progression, and immune signaling.
In this talk, I will present our latest findings, which highlight the remarkable mechanistic diversity within the E3 ligase family. Strikingly, hallmark features of established E3 subtypes can merge with those of newly discovered classes, demonstrating a fluidity in mechanistic principles and opening new possibilities for rethinking the functional scope of known E3 components. Moreover, while some subtypes exhibit clear biochemical signatures, our data reveal that hybrid or even dual enzymatic activities can coexist within a single E3, enabling unexpected modes of functional diversification. A compelling emerging paradigm is the integration of secondary enzymatic modules—such as nucleotide or nucleic acid sensors—whose tightly coordinated activities are fundamental to E3 regulation.