研究人员对BIRC6与caspase-9、HTRA2、SMAC和LC3B等关键凋亡和自噬蛋白的复合物进行了结构功能分析。冷冻电镜结构显示BIRC6形成了一个兆达尔顿的新月形，围绕着一个包含底物蛋白受体位点的空间腔。SMAC的多价结合阻碍了底物结合，阻碍了自噬和凋亡底物的泛素化。基于这些数据，研究人员讨论了BIRC6/SMAC复合物如何作为应激诱导中枢调节细胞凋亡和自噬驱动因子。
据了解，凋亡抑制子蛋白（IAP）与促凋亡蛋白酶结合，使其保持活性并防止细胞死亡。非典型泛素连接酶BIRC6是唯一必要的IAP，另外还起抑制自噬的作用。
附：英文原文
Title: Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex
Author: 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
Issue&Volume: 2023-02-09
Abstract: 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 show 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. Based on these data, we discuss how the BIRC6/SMAC complex can act as a stress-induced hub to regulate apoptosis and autophagy drivers.
DOI: ade8873
Source: https://www.science.org/doi/10.1126/science.ade8873