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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.

Original publication

DOI

10.1126/science.ade8840

Type

Journal article

Journal

Science

Publication Date

17/03/2023

Volume

379

Pages

1112 - 1117

Keywords

Humans, Apoptosis, Caspase 3, Caspase 7, Caspase 9, Cryoelectron Microscopy, Inhibitor of Apoptosis Proteins, Ubiquitin-Protein Ligases, X-Linked Inhibitor of Apoptosis Protein, Catalytic Domain, Protein Multimerization