{"doi":"10.1073/pnas.2408697121","title":"N-degron pathways","abstract":"<jats:p>An N-degron is a degradation signal whose main determinant is a “destabilizing” N-terminal residue of a protein. Specific N-degrons, discovered in 1986, were the first identified degradation signals in short-lived intracellular proteins. These N-degrons are recognized by a ubiquitin-dependent proteolytic system called the Arg/N-degron pathway. Although bacteria lack the ubiquitin system, they also have N-degron pathways. Studies after 1986 have shown that all 20 amino acids of the genetic code can act, in specific sequence contexts, as destabilizing N-terminal residues. Eukaryotic proteins are targeted for the conditional or constitutive degradation by at least five N-degron systems that differ both functionally and mechanistically: the Arg/N-degron pathway, the Ac/N-degron pathway, the Pro/N-degron pathway, the fMet/N-degron pathway, and the newly named, in this perspective, GASTC/N-degron pathway (GASTC = Gly, Ala, Ser, Thr, Cys). I discuss these systems and the expanded terminology that now encompasses the entire gamut of known N-degron pathways.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":607742,"datarank":0.6329261557764161,"base_score":4.219507705176107,"endowment":4.219507705176107,"self_citation_contribution":0.6329261557764161,"citation_network_contribution":0.0,"self_endowment_contribution":0.6329261557764161,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":67,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":345477,"name":"Alexander Varshavsky","orcid":"0000-0002-4011-258X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"N-degron pathways","abstract":"<jats:p>An N-degron is a degradation signal whose main determinant is a “destabilizing” N-terminal residue of a protein. Specific N-degrons, discovered in 1986, were the first identified degradation signals in short-lived intracellular proteins. These N-degrons are recognized by a ubiquitin-dependent proteolytic system called the Arg/N-degron pathway. Although bacteria lack the ubiquitin system, they also have N-degron pathways. Studies after 1986 have shown that all 20 amino acids of the genetic code can act, in specific sequence contexts, as destabilizing N-terminal residues. Eukaryotic proteins are targeted for the conditional or constitutive degradation by at least five N-degron systems that differ both functionally and mechanistically: the Arg/N-degron pathway, the Ac/N-degron pathway, the Pro/N-degron pathway, the fMet/N-degron pathway, and the newly named, in this perspective, GASTC/N-degron pathway (GASTC = Gly, Ala, Ser, Thr, Cys). I discuss these systems and the expanded terminology that now encompasses the entire gamut of known N-degron pathways.</jats:p>","is_dataset_classified":null,"base_score":4.189654742026425,"endowment":4.189654742026425,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39264755","pmcid":"PMC11441550","openalex_id":"https://openalex.org/W4402478673","authors":[],"funders":[{"funder_name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","grant_id":"DK039520","title":null},{"funder_name":"HHS | NIH | National Institute of General Medical Sciences","grant_id":"GM031530","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM031530","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R37 DK039520","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK039520","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R56 DK039520","title":null}],"total_grants":6,"fwci":11.7425,"citation_percentile":0.99186004,"influential_citations":0,"citation_trend":[{"year":2024,"count":5},{"year":2025,"count":46},{"year":2026,"count":14}],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.1073/pnas.2408697121","host_type":"journal"},{"url":"https://doi.org/10.1073/pnas.2408697121","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.2408697121","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39264755","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11441550","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11441550/pdf/pnas.202408697.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11441550","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11441550?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Peptidase Inhibition and Analysis","Ubiquitin and proteasome pathways","Cancer-related gene regulation"],"mesh_terms":["Degrons","Animals","Humans","Proteins","Signal Transduction","Ubiquitin","Proteolysis"],"keywords":["Degron","Ubiquitin","Cell biology","Chemistry","Biology","Post-translational regulation","Biochemistry","Ubiquitin ligase","Phosphorylation","Gene","N-terminal","Proteolysis","Proteasome"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-30T06:56:58.278388Z","pmid":null,"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":[]}