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LMB Seminar: Structural basis of how the BIRC6/SMAC complex regulates apoptosis and autophagy

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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. Little is known of the mechanism how BIRC6 fulfills these two roles. Here, 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-EM structures show 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. These data reveal the molecular mechanism of how the stress induced BIRC6 /SMAC complex assembles a central hub regulating apoptosis and autophagy

This talk is part of the MRC LMB Seminar list series.

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