Degrons: defining the rules of protein degradation.

Degrons are pivotal components of the ubiquitin-proteasome system, serving as the recognition determinants through which E3 ubiquitin ligases identify their substrates. Degrons have central roles in both protein quality control and intracellular signalling pathways, and mutations that dysregulate degron activity are associated with a wide range of diseases, including cancer, immunological disorders and neurodegeneration. The number of well-defined degrons remains sparse relative to the ~600 E3 ubiquitin ligases encoded in the human genome. Recent advances in high-throughput degron discovery technologies have accelerated progress in this area, expanding the number of N- and C-terminal degrons, internal degrons and ubiquitin-independent degrons defined experimentally at high resolution. In this Review, we discuss the latest insights into the molecular mechanisms through which degrons act, their functional importance and their relevance in human disease, and consider how bifunctional molecules harness degrons to enable targeted protein degradation for therapeutic benefit.