Dataset Information

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): Orbitrap Fusion

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

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Dataset's files

Source:

			Action	DRS
	BIRC6_AP_MS.pg_matrix.tsv	Tabular
	FL1438b_MSQ2320_20220315_DIA_BIRC6_APMS_1.raw	Raw
	FL1438b_MSQ2320_20220315_DIA_BIRC6_APMS_2.raw	Raw
	FL1438b_MSQ2320_20220315_DIA_BIRC6_APMS_3.raw	Raw
	FL1438b_MSQ2320_20220315_DIA_CTRL_APMS_1.raw	Raw

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Publications

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

Dietz Larissa L Ellison Cara J CJ Riechmann Carlos C Cassidy C Keith CK Felfoldi F Daniel FD Pinto-Fernández Adán A Kessler Benedikt M BM Elliott Paul R PR

Science (New York, N.Y.) 20230209 6637

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 ubiquitin ...[more]

PMID: 36758106

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