{"doi":"10.1016/j.celrep.2023.113100","title":"Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10","abstract":"In ribosome-associated quality control (RQC), nascent polypeptides produced by interrupted translation are modified with C-terminal polyalanine tails (\"Ala-tails\") that function outside ribosomes to induce ubiquitylation by E3 ligases Pirh2 (p53-induced RING-H2 domain-containing) or CRL2 (Cullin-2 RING ligase2)-KLHDC10. Here, we investigate the molecular basis of Ala-tail function using biochemical and in silico approaches. We show that Pirh2 and KLHDC10 directly bind to Ala-tails and that structural predictions identify candidate Ala-tail-binding sites, which we experimentally validate. The degron-binding pockets and specific pocket residues implicated in Ala-tail recognition are conserved among Pirh2 and KLHDC10 homologs, suggesting that an important function of these ligases across eukaryotes is in targeting Ala-tailed substrates. Moreover, we establish that the two Ala-tail-binding pockets have convergently evolved, either from an ancient module of bacterial provenance (Pirh2) or via tinkering of a widespread C-degron-recognition element (KLHDC10). These results shed light on the recognition of a simple degron sequence and the evolution of Ala-tail proteolytic signaling.","journal":"Cell Reports","year":2023,"id":336544,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"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":77615,"name":"A. Maxwell Burroughs","orcid":"0000-0002-2229-8771","position":1,"is_corresponding":false},{"id":1066991,"name":"Mohit Misra","orcid":"0000-0001-6309-8066","position":2,"is_corresponding":false},{"id":456092,"name":"Federico Cerullo","orcid":"0000-0002-6042-7810","position":3,"is_corresponding":false},{"id":997513,"name":"Carlos Costas‐Insua","orcid":"0000-0003-3446-6899","position":4,"is_corresponding":false},{"id":1067353,"name":"Hao‐Chih Hung","orcid":null,"position":5,"is_corresponding":false},{"id":407132,"name":"Ivan Đikić","orcid":"0000-0001-8156-9511","position":6,"is_corresponding":false},{"id":286376,"name":"L. Aravind","orcid":"0000-0003-0771-253X","position":7,"is_corresponding":false},{"id":281494,"name":"Claudio A.P. Joazeiro","orcid":"0000-0003-1433-8013","position":8,"is_corresponding":false},{"id":645143,"name":"Pratik Rajendra Patil","orcid":"0000-0002-8913-9134","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T01:10:17.243221Z","pmid":"37676773","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":[]}