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

• DOI: 10.1126/science.ade8873
• Publication Date: 2023-02-09T19:00:09Z
• Authors: Julian F. Ehrmann; Daniel B. Grabarczyk; Maria Heinke; Luiza Deszcz; Robert Kurzbauer; Otto Hudecz; Alexandra Shulkina; Rebeca Gogova; Anton Meinhart; Gijs A. Versteeg; Tim Clausen
• Keywords: 0301 basic medicine; Cryoelectron Microscopy; Ubiquitination; Apoptosis; 106023 Molecular biology; High-Temperature Requirement A Serine Peptidase 2; Inhibitor of Apoptosis Proteins; 3. Good health; Mitochondrial Proteins; 03 medical and health sciences; 106023 Molekularbiologie; Autophagy; Humans; 106052 Zellbiologie; Protein Multimerization; 106052 Cell biology; Apoptosis Regulatory Proteins

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.