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

ABSTRACT: Certain Inhibitors of apoptosis (IAP) family members are sentinel proteins preventing untimely cell death by inhibiting caspases. Antagonists including second mitochondria-derived activator of caspase (SMAC) regulate IAPs, driving cell death. Baculoviral IAP repeat-containing protein 6 (BIRC6), a giant IAP with dual E2/E3 ubiquitin ligase activity, regulates programmed cell death through unknown mechanisms. We show BIRC6 directly restricts executioner caspases-3 and -7, and ubiquitinates caspases-3, -7 and -9 working exclusively with non canonical E1, UBA6. Importantly, we show SMAC supresses both mechanisms. Cryo-electron microscopy structures of BIRC6 alone and in complex with SMAC reveals BIRC6 is an anti parallel dimer juxtaposing the substrate-binding module against the catalytic domain. Furthermore, we discover SMAC multi-site binding to BIRC6 results in a sub-nanomolar affinity interaction, enabling SMAC to competitively displace caspases thus antagonising BIRC6 anti-caspase function.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Adan Pinto-Fernandez  

LAB HEAD: Adan Pinto-Fernandez

PROVIDER: PXD039954 | Pride | 2023-03-08

REPOSITORIES: Pride