{"doi":"10.1101/2022.08.19.504532","title":"Structures of BIRC6-Client Complexes Provide Mechanism of Smac-Mediated Release of Caspases","abstract":"Summary Apoptosis is tightly regulated and essential for metazoan development 1, 2 . Excessive apoptosis contributes to neurodegenerative disease, while diminished apoptosis can lead to inflammation and cancer 3 . Inhibitor of apoptosis (IAP) proteins are the principal actors that restrain apoptotic activity and are thus attractive therapeutic targets 4 . IAPs in turn are regulated by mitochondria-derived pro-apoptotic factors such as Smac and HtrA2 4 . Here, through a series of cryo-electron microscopy (cryo-EM) structures of full-length baculoviral IAP repeat-containing protein 6 (BIRC6) bound to Smac, caspase-3, caspase-7 and HtrA2, we provide the molecular basis for BIRC6-mediated caspase inhibition and its release by Smac. We demonstrate that BIRC6 cooperates preferentially with the non-canonical E1 enzyme UBA6 to ubiquitylate caspases and that caspase ubiquitylation is effectively inhibited by Smac through near-irreversible interactions. The dimeric arrangement of BIRC6 resolves the long-standing question of how the evolutionarily conserved single-BIR domain IAPs sequester caspases and how Smac binding antagonizes IAPs. This collection of BIRC6 structures provides critical insights into IAP-mediated apoptosis regulation, relevant for the development of current and future apoptosis-targeting cancer therapeutics.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":310957,"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":0.9536,"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":562441,"name":"Cyrus Y. Jin","orcid":null,"position":1,"is_corresponding":false},{"id":262829,"name":"Eric S. Fischer","orcid":"0000-0001-7337-6306","position":2,"is_corresponding":false},{"id":561748,"name":"Moritz Hunkeler","orcid":"0000-0003-0246-1188","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T00:33:24.451129Z","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":[]}