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TitleStructures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases.
Journal, issue, pagesScience, Vol. 379, Issue 6637, Page 1105-1111, Year 2023
Publish dateMar 17, 2023
AuthorsMoritz Hunkeler / Cyrus Y Jin / Eric S Fischer /
PubMed AbstractTight 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 ...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.
External linksScience / PubMed:36758104
MethodsEM (single particle)
Resolution1.98 - 3.44 Å
Structure data

27832

8e2d

EMDB-27832, PDB-8e2d:
Cryo-EM structure of BIRC6 (consensus)
Method: EM (single particle) / Resolution: 2.07 Å

27833

8e2e

EMDB-27833, PDB-8e2e:
Cryo-EM structure of helical arch of BIRC6 (from local refinement 1)
Method: EM (single particle) / Resolution: 1.98 Å

27834

8e2f

EMDB-27834, PDB-8e2f:
Cryo-EM structure of N-terminal arm of BIRC6 (from local refinement 2)
Method: EM (single particle) / Resolution: 2.47 Å

27835

8e2g

EMDB-27835, PDB-8e2g:
Cryo-EM structure of N-terminal arm (aa68-966) of BIRC6 (from local refinement 3)
Method: EM (single particle) / Resolution: 2.99 Å

27836

8e2h

EMDB-27836, PDB-8e2h:
Cryo-EM structure of C-terminal arm of BIRC6 (from local refinement 4)
Method: EM (single particle) / Resolution: 2.3 Å

27837

8e2i

EMDB-27837, PDB-8e2i:
Cryo-EM structure of BIRC6/Smac
Method: EM (single particle) / Resolution: 3.04 Å

27838

8e2j

EMDB-27838, PDB-8e2j:
Cryo-EM structure of BIRC6/Smac (from local refinement 1)
Method: EM (single particle) / Resolution: 3.44 Å

EMDB-27839: Cryo-EM density of BIRC6/casp-3 (clusters)
Method: EM (single particle) / Resolution: 2.82 Å

EMDB-27840: Cryo-EM density of BIRC6/casp-7 (clusters)
Method: EM (single particle) / Resolution: 3.01 Å

27841

8e2k

EMDB-27841, PDB-8e2k:
Cryo-EM structure of BIRC6/HtrA2-S306A
Method: EM (single particle) / Resolution: 3.21 Å

Chemicals

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
KeywordsLIGASE / Ubiquitin / E3 ligase / Apoptosis / Autophagy / IAP

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