8ato

Structure of the giant inhibitor of apoptosis, BIRC6 bound to the regulator SMACStructure of the giant inhibitor of apoptosis, BIRC6 bound to the regulator SMAC

Structural highlights

8ato is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DBLOH_HUMAN Defects in DIABLO are the cause of deafness autosomal dominant type 64 (DFNA64) [MIM:614152. DFNA64 is a form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.^[1]

Function

DBLOH_HUMAN Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). Inhibits the activity of BIRC6/bruce by inhibiting its binding to caspases. Isoform 3 attenuates the stability and apoptosis-inhibiting activity of XIAP/BIRC4 by promoting XIAP/BIRC4 ubiquitination and degradation through the ubiquitin-proteasome pathway. Isoform 3 also disrupts XIAP/BIRC4 interacting with processed caspase-9 and promotes caspase-3 activation. Isoform 1 is defective in the capacity to down-regulate the XIAP/BIRC4 abundance.^[2] ^[3] ^[4]

Publication Abstract from PubMed

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.

Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6.,Dietz L, Ellison CJ, Riechmann C, Cassidy CK, Felfoldi FD, Pinto-Fernandez A, Kessler BM, Elliott PR Science. 2023 Mar 17;379(6637):1112-1117. doi: 10.1126/science.ade8840. Epub 2023 , Feb 9. PMID:36758106^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cheng J, Zhu Y, He S, Lu Y, Chen J, Han B, Petrillo M, Wrzeszczynski KO, Yang S, Dai P, Zhai S, Han D, Zhang MQ, Li W, Liu X, Li H, Chen ZY, Yuan H. Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. Am J Hum Genet. 2011 Jul 15;89(1):56-66. doi: 10.1016/j.ajhg.2011.05.027. Epub, 2011 Jun 30. PMID:21722859 doi:10.1016/j.ajhg.2011.05.027
↑ Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000 Jul 7;102(1):33-42. PMID:10929711
↑ Fu J, Jin Y, Arend LJ. Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of X-linked inhibitor of apoptosis protein. J Biol Chem. 2003 Dec 26;278(52):52660-72. Epub 2003 Sep 30. PMID:14523016 doi:10.1074/jbc.M308036200
↑ Bartke T, Pohl C, Pyrowolakis G, Jentsch S. Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Mol Cell. 2004 Jun 18;14(6):801-11. PMID:15200957 doi:10.1016/j.molcel.2004.05.018
↑ Dietz L, Ellison CJ, Riechmann C, Cassidy CK, Felfoldi FD, Pinto-Fernández A, Kessler BM, Elliott PR. Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6. Science. 2023 Mar 17;379(6637):1112-1117. PMID:36758106 doi:10.1126/science.ade8840

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OCA

[1] Cheng J, Zhu Y, He S, Lu Y, Chen J, Han B, Petrillo M, Wrzeszczynski KO, Yang S, Dai P, Zhai S, Han D, Zhang MQ, Li W, Liu X, Li H, Chen ZY, Yuan H. Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. Am J Hum Genet. 2011 Jul 15;89(1):56-66. doi: 10.1016/j.ajhg.2011.05.027. Epub, 2011 Jun 30. PMID:21722859 doi:10.1016/j.ajhg.2011.05.027

[2] Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000 Jul 7;102(1):33-42. PMID:10929711

[3] Fu J, Jin Y, Arend LJ. Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of X-linked inhibitor of apoptosis protein. J Biol Chem. 2003 Dec 26;278(52):52660-72. Epub 2003 Sep 30. PMID:14523016 doi:10.1074/jbc.M308036200

[4] Bartke T, Pohl C, Pyrowolakis G, Jentsch S. Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Mol Cell. 2004 Jun 18;14(6):801-11. PMID:15200957 doi:10.1016/j.molcel.2004.05.018

[5] Dietz L, Ellison CJ, Riechmann C, Cassidy CK, Felfoldi FD, Pinto-Fernández A, Kessler BM, Elliott PR. Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6. Science. 2023 Mar 17;379(6637):1112-1117. PMID:36758106 doi:10.1126/science.ade8840

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