{"doi":"10.1101/2021.02.10.430655","title":"Protomer alignment modulates specificity of RNA substrate recognition by Ire1","abstract":"Abstract The unfolded protein response (UPR) maintains protein folding homeostasis in the endoplasmic reticulum (ER). In metazoan cells, the Ire1 branch of the UPR initiates two functional outputs— non-conventional mRNA splicing and selective mRNA decay (RIDD). By contrast, Ire1 orthologs from Saccharomyces cerevisiae and Schizosaccharomyces pombe are specialized for only splicing or RIDD, respectively. The functional specialization lies in Ire1’s RNase activity, which is either stringently splice-site specific (as in S. cerevisiae ) or promiscuous (as in S. pombe ). Here, we developed an assay that reports on Ire1’s RNase promiscuity. We found that conversion of two amino acids within the RNase domain of S. cerevisiae Ire1 to their S. pombe counterparts rendered it promiscuous. Using biochemical assays and computational modeling, we show that the mutations rewired a pair of salt bridges at Ire1 RNase domain’s dimer interface, changing its protomer alignment. Thus, Ire1 protomer alignment affects its substrates specificity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223087,"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":0,"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":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":704939,"name":"Kelly Crotty","orcid":"0000-0001-8462-5275","position":1,"is_corresponding":false},{"id":764719,"name":"Diego Garrido Ruiz","orcid":"0000-0002-2441-385X","position":2,"is_corresponding":false},{"id":764720,"name":"Mark Voorhies","orcid":"0000-0001-8815-7384","position":3,"is_corresponding":false},{"id":737416,"name":"Carlos Rondón","orcid":"0000-0001-5025-6141","position":4,"is_corresponding":false},{"id":107229,"name":"Anita Sil","orcid":"0000-0002-3987-7534","position":5,"is_corresponding":false},{"id":106699,"name":"R. Dyche Mullins","orcid":"0000-0002-0871-5479","position":6,"is_corresponding":false},{"id":272025,"name":"Matthew P. Jacobson","orcid":"0000-0001-6262-655X","position":7,"is_corresponding":false},{"id":141316,"name":"Jirka Peschek","orcid":"0000-0001-8158-9301","position":8,"is_corresponding":false},{"id":105723,"name":"Peter Walter","orcid":"0000-0002-6849-708X","position":9,"is_corresponding":false},{"id":630432,"name":"Weihan Li","orcid":"0000-0003-4718-1884","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:07.287704Z","pmid":null,"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":[]}