8ATM

Structure of the giant inhibitor of apoptosis, BIRC6 (composite map)

This is a non-PDB format compatible entry.

Summary for 8ATM

• Entry DOI: 10.2210/pdb8atm/pdb
• EMDB information: 15648 15650 15651 15652 15653
• Descriptor: Baculoviral IAP repeat-containing protein 6 (1 entity in total)
• Functional Keywords: e2/e3 ubiquitin ligase, apoptosis
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 1061954.00

Authors

Dietz, L.,Elliott, P.R. (deposition date: 2022-08-23, release date: 2023-03-08, Last modification date: 2024-07-24)

Primary citation

Dietz, L.,Ellison, C.J.,Riechmann, C.,Cassidy, C.K.,Felfoldi, F.D.,Pinto-Fernandez, A.,Kessler, B.M.,Elliott, P.R.
Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6.
Science, 379:1112-1117, 2023

PubMed 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.

PubMed: 36758106
DOI: 10.1126/science.ade8840

Experimental method

ELECTRON MICROSCOPY (3.3 Å)