Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex

• 成果类型: Article
• 署名作者: Ehrmann, Julian F.; Grabarczyk, Daniel B.; Heinke, Maria; Deszcz, Luiza; Kurzbauer, Robert; Hudecz, Otto; Shulkina, Alexandra; Gogova, Rebeca; Meinhart, Anton; Versteeg, Gijs A.; Clausen, Tim
• 署名单位: Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); University of Vienna; Vienna Biocenter (VBC); Medical University of Vienna; Medical University of Vienna; Vienna Biocenter (VBC); Medical University of Vienna; University of Vienna; Vienna Biocenter (VBC); Max F. Perutz Laboratories (MFPL); Medical University of Vienna
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12544
• DOI: 10.1126/science.ade8873
• 发表日期: 2023-03-17
• 页码: 1117-1122
• 关键词: cell-death; iap; protein; binding; bruce; activation; mutations; apollon; diablo; smac

摘要

Inhibitor of apoptosis proteins (IAPs) bind to pro-apoptotic proteases, keeping them inactive and preventing cell death. The atypical ubiquitin ligase BIRC6 is the only essential IAP, additionally functioning as a suppressor of autophagy. We performed a structure-function analysis of BIRC6 in complex with caspase-9, HTRA2, SMAC, and LC3B, which are critical apoptosis and autophagy proteins. Cryo-electron microscopy structures showed that BIRC6 forms a megadalton crescent shape that arcs around a spacious cavity containing receptor sites for client proteins. Multivalent binding of SMAC obstructs client binding, impeding ubiquitination of both autophagy and apoptotic substrates. On the basis of these data, we discuss how the BIRC6/SMAC complex can act as a stress-induced hub to regulate apoptosis and autophagy drivers.