Dark and Dronc activation in Drosophila melanogaster

• 成果类型: Article
• 署名作者: Tian, Lu; Li, Yini; Shi, Yigong
• 署名单位: Tsinghua University; Westlake University; Westlake Laboratory; Westlake University; Westlake University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15421
• DOI: 10.1073/pnas.2312784121
• 发表日期: 2024-02-27
• 关键词: cytochrome-c; caspase activation; cell-death; initiator caspase; atomic-structure; elegans ced-4; apoptosome; apaf-1; mechanism; datp

摘要

The onset of apoptosis is characterized by a cascade of caspase activation, where initiator caspases are activated by a multimeric adaptor complex known as the apoptosome. In Drosophila melanogaster, the initiator caspase Dronc undergoes autocatalytic activation in the presence of the Dark apoptosome. Despite rigorous investigations, the activation mechanism for Dronc remains elusive. Here, we report the cryo- EM structures of an auto- inhibited Dark monomer and a single- layered, multimeric Dark/Dronc complex. Our biochemical analysis suggests that the auto- inhibited Dark oligomerizes upon binding to Dronc, which is sufficient for the activation of both Dark and Dronc. In contrast, the previously observed double- ring Dark apoptosome may represent a non- functional or off- pathway conformation. These findings expand our understanding on the molecular mechanism of apoptosis in Drosophila.