{"doi":"10.1093/nar/gkac739","title":"Global 5′-UTR RNA structure regulates translation of a <i>SERPINA1</i> mRNA","abstract":"SERPINA1 mRNAs encode the protease inhibitor α-1-antitrypsin and are regulated through post-transcriptional mechanisms. α-1-antitrypsin deficiency leads to chronic obstructive pulmonary disease (COPD) and liver cirrhosis, and specific variants in the 5'-untranslated region (5'-UTR) are associated with COPD. The NM_000295.4 transcript is well expressed and translated in lung and blood and features an extended 5'-UTR that does not contain a competing upstream open reading frame (uORF). We show that the 5'-UTR of NM_000295.4 folds into a well-defined multi-helix structural domain. We systematically destabilized mRNA structure across the NM_000295.4 5'-UTR, and measured changes in (SHAPE quantified) RNA structure and cap-dependent translation relative to a native-sequence reporter. Surprisingly, despite destabilizing local RNA structure, most mutations either had no effect on or decreased translation. Most structure-destabilizing mutations retained native, global 5'-UTR structure. However, those mutations that disrupted the helix that anchors the 5'-UTR domain yielded three groups of non-native structures. Two of these non-native structure groups refolded to create a stable helix near the translation initiation site that decreases translation. Thus, in contrast to the conventional model that RNA structure in 5'-UTRs primarily inhibits translation, complex folding of the NM_000295.4 5'-UTR creates a translation-optimized message by promoting accessibility at the translation initiation site.","journal":"Nucleic Acids Research","year":2022,"id":250743,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":5949,"name":"Chase A. Weidmann","orcid":"0000-0002-2941-0500","position":1,"is_corresponding":false},{"id":548631,"name":"Jayashree Kumar","orcid":"0000-0001-6914-748X","position":2,"is_corresponding":false},{"id":601953,"name":"Lela Lackey","orcid":"0000-0003-2163-4005","position":3,"is_corresponding":false},{"id":295952,"name":"Anthony M. Mustoe","orcid":"0000-0001-9346-1559","position":4,"is_corresponding":false},{"id":529553,"name":"Steven Busan","orcid":null,"position":5,"is_corresponding":false},{"id":45256,"name":"Alain Laederach","orcid":"0000-0002-5088-9907","position":6,"is_corresponding":false},{"id":5954,"name":"Kevin M. Weeks","orcid":"0000-0002-6748-9985","position":7,"is_corresponding":false},{"id":893547,"name":"Philip J. Grayeski","orcid":null,"position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"36107773","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":[]}