Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Science. 2023 Mar 17;379(6637):1105-1111. doi: 10.1126/science.ade5750. Epub 2023 Feb 9.
Tight regulation of apoptosis is essential for metazoan development and prevents diseases such as cancer and neurodegeneration. Caspase activation is central to apoptosis, and inhibitor of apoptosis proteins (IAPs) are the principal actors that restrain caspase activity and are therefore attractive therapeutic targets. IAPs, in turn, are regulated by mitochondria-derived proapoptotic factors such as SMAC and HTRA2. Through a series of cryo-electron microscopy structures of full-length human baculoviral IAP repeat-containing protein 6 (BIRC6) bound to SMAC, caspases, and HTRA2, we provide a molecular understanding for BIRC6-mediated caspase inhibition and its release by SMAC. The architecture of BIRC6, together with near-irreversible binding of SMAC, elucidates how the IAP inhibitor SMAC can effectively control a processive ubiquitin ligase to respond to apoptotic stimuli.
细胞凋亡的严格调控对于后生动物的发育至关重要，可预防癌症和神经退行性疾病等疾病。半胱氨酸天冬氨酸蛋白酶（caspase）的激活是细胞凋亡的核心，凋亡抑制蛋白（IAPs）是主要的抑制 caspase 活性的因子，因此成为有吸引力的治疗靶点。反过来，IAPs 又受到线粒体衍生的促凋亡因子如 SMAC 和 HTRA2 的调节。通过一系列全长人杆状病毒 IAP 重复蛋白 6（BIRC6）与 SMAC、半胱天冬酶和 HTRA2 结合的冷冻电子显微镜结构，我们为 BIRC6 介导的半胱天冬酶抑制及其被 SMAC 释放提供了分子理解。BIRC6 的结构以及与 SMAC 的近乎不可逆结合，阐明了 IAP 抑制剂 SMAC 如何能够有效地控制一个连续的泛素连接酶来响应凋亡刺激。
