{"doi":"10.1016/j.molcel.2025.11.017","title":"HYPK promotes N-terminal protein acetylation through rapid ribosome exchange of NatA","abstract":"Numerous protein biogenesis factors cotranslationally facilitate the maturation of nascent proteins. Among them, N-terminal acetyltransferase A (NatA) acetylates the N terminus of ∼40% of the eukaryotic proteome. NatA is bound to Huntingtin-interacting protein K (HYPK), which inhibits NatA activity in vitro but enhances function in vivo. Here, kinetic and in-cell measurements resolve this paradox, showing that HYPK acts as a ribosome exchange factor for NatA. Without HYPK, hyper-tight ribosome binding prevents NatA from accessing additional ribosomes following each round of acetylation. HYPK accelerates NatA dissociation from the ribosome to license multiple turnovers, allowing a sub-stoichiometric level of this enzyme to globally acetylate the nascent proteome. Our results uncover a previously unidentified function of HYPK and demonstrate that a \"Goldilocks\" zone of ribosome interaction kinetics is required for cotranslational protein biogenesis machineries to act on all translating ribosomes in the cell.","journal":"Molecular Cell","year":2025,"id":549327,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1421282,"name":"Ziyi Fan","orcid":"0000-0003-3793-2445","position":1,"is_corresponding":false},{"id":1443527,"name":"Inayat Ullah Irshad","orcid":"0000-0003-2868-3600","position":2,"is_corresponding":false},{"id":323020,"name":"Edward P. O’Brien","orcid":"0000-0001-9809-3273","position":3,"is_corresponding":false},{"id":523896,"name":"Ajeet K. Sharma","orcid":"0000-0002-2819-1668","position":4,"is_corresponding":false},{"id":17827,"name":"Rachel Green","orcid":"0000-0001-9337-2003","position":5,"is_corresponding":false},{"id":344909,"name":"Shu‐ou Shan","orcid":"0000-0002-6526-1733","position":6,"is_corresponding":false},{"id":714171,"name":"Alfred M. Lentzsch","orcid":"0000-0002-8150-0511","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:54:07.823422Z","pmid":"41380682","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":[]}