Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6

• 成果类型: Article
• 署名作者: Dietz, Larissa; Ellison, Cara J.; Riechmann, Carlos; Cassidy, C. Keith; Felfoldi, F. Daniel; Pinto-Fernandez, Adan; Kessler, Benedikt M.; Elliott, Paul R.
• 署名单位: University of Oxford; University of Oxford; University of Oxford; Chinese Academy of Medical Sciences - Peking Union Medical College; University of London; University College London
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8625
• DOI: 10.1126/science.ade8840
• 发表日期: 2023-03-17
• 页码: 1112-+
• 关键词: apoptosis protein; iap; bruce; xiap; activation; ciap1; gene; mechanism; apollon; p53

摘要

Certain inhibitor of apoptosis (IAP) family members are sentinel proteins that prevent untimely cell death by inhibiting caspases. Antagonists, including second mitochondria-derived activator of caspases (SMAC), regulate IAPs and drive cell death. Baculoviral IAP repeat-containing protein 6 (BIRC6), a giant IAP with dual E2 and E3 ubiquitin ligase activity, regulates programmed cell death through unknown mechanisms. We show that BIRC6 directly restricts executioner caspase-3 and-7 and ubiquitinates caspase-3,-7, and-9, working exclusively with noncanonical E1, UBA6. Notably, we show that SMAC suppresses both mechanisms. Cryo-electron microscopy structures of BIRC6 alone and in complex with SMAC reveal that BIRC6 is an antiparallel dimer juxtaposing the substrate-binding module against the catalytic domain. Furthermore, we discover that SMAC multisite binding to BIRC6 results in a subnanomolar affinity interaction, enabling SMAC to competitively displace caspases, thus antagonizing BIRC6 anticaspase function.