8e2e

From Proteopedia

Cryo-EM structure of helical arch of BIRC6 (from local refinement 1)

Structural highlights

8e2e 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 1.98Å
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

Tight regulation of apoptosis is essential for metazoan development and prevents diseases such as cancer and neurodegeneration. Caspase activation is central to apoptosis, and inhibitor of apoptosis proteins (IAPs) are the principal actors that restrain caspase activity and are therefore attractive therapeutic targets. IAPs, in turn, are regulated by mitochondria-derived proapoptotic factors such as SMAC and HTRA2. Through a series of cryo-electron microscopy structures of full-length human baculoviral IAP repeat-containing protein 6 (BIRC6) bound to SMAC, caspases, and HTRA2, we provide a molecular understanding for BIRC6-mediated caspase inhibition and its release by SMAC. The architecture of BIRC6, together with near-irreversible binding of SMAC, elucidates how the IAP inhibitor SMAC can effectively control a processive ubiquitin ligase to respond to apoptotic stimuli.

Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases.,Hunkeler M, Jin CY, Fischer ES Science. 2023 Mar 17;379(6637):1105-1111. doi: 10.1126/science.ade5750. Epub 2023 , Feb 9. PMID:36758104^[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
↑ Hunkeler M, Jin CY, Fischer ES. Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases. Science. 2023 Mar 17;379(6637):1105-1111. PMID:36758104 doi:10.1126/science.ade5750