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-Structure paper
タイトル | Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6. |
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ジャーナル・号・ページ | Science, Vol. 379, Issue 6637, Page 1112-1117, Year 2023 |
掲載日 | 2023年3月17日 |
著者 | Larissa Dietz / Cara J Ellison / Carlos Riechmann / C Keith Cassidy / F Daniel Felfoldi / Adán Pinto-Fernández / Benedikt M Kessler / Paul R Elliott / |
PubMed 要旨 | 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 ...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. |
リンク | Science / PubMed:36758106 |
手法 | EM (単粒子) |
解像度 | 3.0 - 3.3 Å |
構造データ | EMDB-15648: Structure of the giant inhibitor of apoptosis, BIRC6 (multibody map 1) EMDB-15650: Structure of the giant inhibitor of apoptosis, BIRC6 (multibody map 2) EMDB-15651: Structure of the giant inhibitor of apoptosis, BIRC6 (multibody map 3) EMDB-15652: Structure of the giant inhibitor of apoptosis, BIRC6 (homogenous refinement) EMDB-15653, PDB-8atm: EMDB-15654, PDB-8ato: |
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キーワード | APOPTOSIS / E2/E3 ubiquitin ligase |