{"doi":"10.1073/pnas.2007085117","title":"Recognition of nonproline N-terminal residues by the Pro/N-degron pathway","abstract":"Eukaryotic N-degron pathways are proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, and to target these proteins for degradation by the 26S proteasome or autophagy. GID4, a subunit of the GID ubiquitin ligase, is the main recognition component of the proline (Pro)/N-degron pathway. GID4 targets proteins through their Nt-Pro residue or a Pro at position 2, in the presence of specific downstream sequence motifs. Here we show that human GID4 can also recognize hydrophobic Nt-residues other than Pro. One example is the sequence Nt-IGLW, bearing Nt-Ile. Nt-IGLW binds to wild-type human GID4 with a K d of 16 μM, whereas the otherwise identical Nt-Pro–bearing sequence PGLW binds to GID4 more tightly, with a K d of 1.9 μM. Despite this difference in affinities of GID4 for Nt-IGLW vs. Nt-PGLW, we found that the GID4-mediated Pro/N-degron pathway of the yeast Saccharomyces cerevisiae can target an Nt-IGLW–bearing protein for rapid degradation. We solved crystal structures of human GID4 bound to a peptide bearing Nt-Ile or Nt-Val. We also altered specific residues of human GID4 and measured the affinities of resulting mutant GID4s for Nt-IGLW and Nt-PGLW, thereby determining relative contributions of specific GID4 residues to the GID4-mediated recognition of Nt-Pro vs. Nt-residues other than Pro. These and related results advance the understanding of targeting by the Pro/N-degron pathway and greatly expand the substrate recognition range of the GID ubiquitin ligase in both human and yeast cells.","journal":"Proceedings of the National Academy of Sciences","year":2020,"id":65340,"datarank":0.6166310796259968,"base_score":4.110873864173311,"endowment":4.110873864173311,"self_citation_contribution":0.6166310796259968,"citation_network_contribution":0.0,"self_endowment_contribution":0.6166310796259968,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":60,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9508,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":345475,"name":"Shun‐Jia Chen","orcid":"0000-0002-5489-4930","position":1,"is_corresponding":false},{"id":345476,"name":"Artem Melnykov","orcid":"0000-0002-4733-4249","position":2,"is_corresponding":false},{"id":346622,"name":"Sara Weirich","orcid":null,"position":3,"is_corresponding":false},{"id":346623,"name":"Kelly Sun","orcid":null,"position":4,"is_corresponding":false},{"id":247179,"name":"Albert Jeltsch","orcid":"0000-0001-6113-9290","position":5,"is_corresponding":false},{"id":345477,"name":"Alexander Varshavsky","orcid":"0000-0002-4011-258X","position":6,"is_corresponding":false},{"id":345478,"name":"Jinrong Min","orcid":"0000-0001-5210-3130","position":7,"is_corresponding":false},{"id":345474,"name":"Dong Cheng","orcid":"0000-0002-2891-8759","position":0,"is_corresponding":true}],"reference_count":125,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:13:23.327603Z","pmid":"32513738","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":[]}