{"doi":"10.1016/j.molcel.2023.08.022","title":"Elucidation of E3 ubiquitin ligase specificity through proteome-wide internal degron mapping","abstract":"The ubiquitin-proteasome system plays a critical role in biology by regulating protein degradation. Despite their importance, precise recognition specificity is known for a few of the 600 E3s. Here, we establish a two-pronged strategy for identifying and mapping critical residues of internal degrons on a proteome-scale in HEK-293T cells. We employ global protein stability profiling combined with machine learning to identify 15,800 peptides likely to contain sequence-dependent degrons. We combine this with scanning mutagenesis to define critical residues for over 5,000 predicted degrons. Focusing on Cullin-RING ligase degrons, we generated mutational fingerprints for 219 degrons and developed DegronID, a computational algorithm enabling the clustering of degron peptides with similar motifs. CRISPR analysis enabled the discovery of E3-degron pairs, of which we uncovered 16 pairs that revealed extensive degron variability and structural determinants. We provide the visualization of these data on the public DegronID data browser as a resource for future exploration.","journal":"Molecular Cell","year":2023,"id":320651,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":108417,"name":"Brandon Sie","orcid":"0000-0001-9405-1850","position":1,"is_corresponding":false},{"id":618175,"name":"Aiquan Chang","orcid":"0000-0002-9482-0979","position":2,"is_corresponding":false},{"id":108415,"name":"Yumei Leng","orcid":"0000-0003-2512-9284","position":3,"is_corresponding":false},{"id":1016939,"name":"Christopher Nardone","orcid":"0000-0002-1705-5310","position":4,"is_corresponding":false},{"id":108413,"name":"Richard T. Timms","orcid":"0000-0001-7275-597X","position":5,"is_corresponding":false},{"id":108430,"name":"Stephen J. Elledge","orcid":"0000-0001-7923-6283","position":6,"is_corresponding":false},{"id":1031853,"name":"Zhiqian Zhang","orcid":"0000-0002-7867-9653","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T01:07:27.434133Z","pmid":"37738965","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}