DEGRONOPEDIA: A practical guide to identifying and targeting protein degrons

Degrons are recognition motifs mediating substrate binding to E3 ubiquitin ligases within the ubiquitin-proteasome system, driving protein ubiquitination and degradation. These motifs, located at protein N- and C-termini or within internal regions, are essential for maintaining proteostasis. Effective degradation relies on a tripartite architecture: a degron motif, a ubiquitination site, and a proteasomal unwinding seed. This chapter introduces DEGRONOPEDIA, a web server for identifying and predicting degrons across eukaryotic proteomes. It integrates machine learning, solvent accessibility modeling, and proteolysis simulations to analyze degrons in sequential and structural contexts. We provide detailed guidance on its workflow and applications, highlighting its role in studying terminal and internal degrons.