8atm

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

Structural highlights

8atm is a 2 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 3.3Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BIRC6_HUMAN Anti-apoptotic protein which can regulate cell death by controlling caspases and by acting as an E3 ubiquitin-protein ligase. Has an unusual ubiquitin conjugation system in that it could combine in a single polypeptide, ubiquitin conjugating (E2) with ubiquitin ligase (E3) activity, forming a chimeric E2/E3 ubiquitin ligase. Its tragets include CASP9 and DIABLO/SMAC. Acts as an inhibitor of CASP3, CASP7 and CASP9. Important regulator for the final stages of cytokinesis. Crucial for normal vesicle targeting to the site of abscission, but also for the integrity of the midbody and the midbody ring, and its striking ubiquitin modification.^[1] ^[2] ^[3]

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^[4]

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

References

↑ Qiu XB, Markant SL, Yuan J, Goldberg AL. Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis. EMBO J. 2004 Feb 25;23(4):800-10. Epub 2004 Feb 12. PMID:14765125 doi:10.1038/sj.emboj.7600075
↑ 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
↑ Pohl C, Jentsch S. Final stages of cytokinesis and midbody ring formation are controlled by BRUCE. Cell. 2008 Mar 7;132(5):832-45. doi: 10.1016/j.cell.2008.01.012. PMID:18329369 doi:http://dx.doi.org/10.1016/j.cell.2008.01.012
↑ 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

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Qiu XB, Markant SL, Yuan J, Goldberg AL. Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis. EMBO J. 2004 Feb 25;23(4):800-10. Epub 2004 Feb 12. PMID:14765125 doi:10.1038/sj.emboj.7600075

[2] 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

[3] Pohl C, Jentsch S. Final stages of cytokinesis and midbody ring formation are controlled by BRUCE. Cell. 2008 Mar 7;132(5):832-45. doi: 10.1016/j.cell.2008.01.012. PMID:18329369 doi:http://dx.doi.org/10.1016/j.cell.2008.01.012

[4] 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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