{"doi":"10.1016/j.jbc.2025.110415","title":"Molecular choreography of E1 enzymes in ubiquitin-like protein cascades: New insights into dynamics and specificity","abstract":"In 2004, Aaron Ciechanover, Avram Hershko, and Irwin Rose were awarded the Nobel Prize in Chemistry for their groundbreaking work uncovering the stepwise, ATP-dependent degradation of cellular proteins. These studies laid the foundation for understanding ubiquitin and ubiquitin-like proteins (Ubls), an evolutionary conserved family of modifiers that mediate diverse cellular processes. The ubiquitin/Ubl system operates through a reaction cascade involving E1 activating, E2 conjugating, and E3 ligating enzymes. As the initiating enzymes, E1s catalyze Ubl adenylation, thiolation, and thioester transfer to their cognate E2s. Despite their conserved architecture, E1s exhibit strict specificity for different Ubls and E2s, a critical feature for maintaining cellular homeostasis. While the molecular mechanisms underlying E1 interactions and activities remain incompletely understood, structural studies have provided key insights into the dynamic changes that accompany Ubl activation and transfer. This review highlights recent structures that build upon foundational biochemical research, elucidating the determinants of activity, specificity, and novel regulatory mechanisms governing E1 enzymes. We examine how conformational changes drive the transition from an adenylate-competent to a thioester-competent state and how these rearrangements facilitate interactions with Ubls and E2s while advancing the reaction cycle. Additionally, we explore recent insights into a prokaryotic E1-E2-like fusion that is structurally homologous to the noncanonical eukaryotic E1 ATG7, revealing its role in activating and conjugating a non-Ubl substrate and its implications for the evolutionarily trajectory of Ubl cascades. Finally, we discuss the current landscape of E1 inhibitors under investigation as potential anticancer therapies, as well as prospects for future investigations.","journal":"Journal of Biological Chemistry","year":2025,"id":513897,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"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":1375711,"name":"Pirouz Ebadi","orcid":"0000-0001-5984-9840","position":1,"is_corresponding":false},{"id":227437,"name":"Shaun K. Olsen","orcid":"0000-0002-1265-7101","position":2,"is_corresponding":false},{"id":1279605,"name":"Caleb M. Stratton","orcid":null,"position":0,"is_corresponding":true}],"reference_count":247,"raw_metadata":null,"created_at":"2026-07-19T02:48:23.284782Z","pmid":"40570956","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":[]}