Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6.
Science
; 379(6637): 1112-1117, 2023 03 17.
Article
em En
| MEDLINE
| ID: mdl-36758106
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Ubiquitina-Proteína Ligases
/
Proteínas Inibidoras de Apoptose
/
Caspase 3
/
Caspase 7
/
Caspase 9
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Reino Unido