A near-complete map of human cytosolic degrons and their relevance for disease

Degrons are short protein segments that direct proteins for degradation via the ubiquitin-proteasome system, ensuring the removal of signaling proteins and clearance of misfolded proteins. We have performed a large-scale screen of more than 200,000 30-residue peptides from more than 5000 human cytosolic proteins, achieving 99.7% coverage. We find that 19% of peptides act as strong degrons, 30% as intermediate, and 51% as non-degrons. We identify both known and previously unidentified degradation signals and show that most depend on the E1 ubiquitin-activating enzyme and the proteasome. Structural mapping shows that many degrons are buried and likely become active upon protein unfolding. Training of a machine learning model allowed us to describe the degron properties and predict the cellular abundance of missense variants that operate by forming degrons in exposed and disordered protein regions, thus providing a mechanism of pathogenicity for germline coding variants at such positions.