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TitleMolecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 891, Year 2024
Publish dateJan 30, 2024
AuthorsShuo-Shuo Liu / Tian-Xia Jiang / Fan Bu / Ji-Lan Zhao / Guang-Fei Wang / Guo-Heng Yang / Jie-Yan Kong / Yun-Fan Qie / Pei Wen / Li-Bin Fan / Ning-Ning Li / Ning Gao / Xiao-Bo Qiu /
PubMed AbstractProcaspase 9 is the initiator caspase for apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor-of-Apoptosis Protein BIRC6/BRUCE/Apollon inhibits both ...Procaspase 9 is the initiator caspase for apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor-of-Apoptosis Protein BIRC6/BRUCE/Apollon inhibits both apoptosis and autophagy by promoting ubiquitylation of proapoptotic factors and the key autophagic protein LC3, respectively. Here we show that BIRC6 forms an anti-parallel U-shaped dimer with multiple previously unannotated domains, including a ubiquitin-like domain, and the proapoptotic factor Smac/DIABLO binds BIRC6 in the central cavity. Notably, Smac outcompetes the effector caspase 3 and the pro-apoptotic protease HtrA2, but not procaspase 9, for binding BIRC6 in cells. BIRC6 also binds LC3 through its LC3-interacting region, probably following dimer disruption of this BIRC6 region. Mutation at LC3 ubiquitylation site promotes autophagy and autophagic degradation of BIRC6. Moreover, induction of autophagy promotes autophagic degradation of BIRC6 and caspase 9, but not of other effector caspases. These results are important to understand how the balance between apoptosis and autophagy is regulated under pathophysiological conditions.
External linksNat Commun / PubMed:38291026 / PubMed Central
MethodsEM (single particle)
Resolution3.5 - 6.0 Å
Structure data

EMDB-35758: Cryo-EM structure of mouse BIRC6, N-terminal section optimized
Method: EM (single particle) / Resolution: 6.0 Å

35759

8ivq

EMDB-35759, PDB-8ivq:
Cryo-EM structure of mouse BIRC6, Global map
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-35760: Cryo-EM structure of mouse BIRC6, with endogenous Smac binding
Method: EM (single particle) / Resolution: 4.7 Å

EMDB-38461: Cryo-EM structure of mouse BIRC6, Core region
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-38462: Cryo-EM structure of mouse BIRC6, Half map of the core region
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-38464: Cryo-EM structure of mouse BIRC6, Composite map
Method: EM (single particle) / Resolution: 3.5 Å

Source
  • mus musculus (house mouse)
KeywordsAPOPTOSIS / Inhibitor of apoptosis protein / BIRC6 / Smac

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