期刊
MOLECULAR CELL
卷 82, 期 24, 页码 4712-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2022.10.032
关键词
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资金
- National Key Research and Development Programs of China [2021YFD1800404, 2018YFA0508000]
- National Natural Science Foundation of China [32270197, 32270061]
- Shenzhen Science and Technology Program [KQTD20200909113758004, JSGG20210901145200002, JCYJ 20210324115611032]
- HZAU-AGIS Cooperation Fund [SZYJY2022023]
This study reveals the multistep enzymatic mechanism of CopC-catalyzed arginine ADPR deacylization in resisting bacterial infections, providing a structural framework for understanding the molecular basis of this process.
Programmed cell death and caspase proteins play a pivotal role in host innate immune response combating pathogen infections. Blocking cell death is employed by many bacterial pathogens as a universal virulence strategy. CopC family type III effectors, including CopC from an environmental pathogen Chromobacterium violaceum, utilize calmodulin (CaM) as a co-factor to inactivate caspases by arginine ADPR deacylization. However, the molecular basis of the catalytic and substrate/co-factor binding mechanism is unknown. Here, we determine successive cryo-EM structures of CaM-CopC-caspase-3 ternary complex in pre -reac-tion, transition, and post-reaction states, which elucidate a multistep enzymatic mechanism of CopC-cata-lyzed ADPR deacylization. Moreover, we capture a snapshot of the detachment of modified caspase-3 from CopC. These structural insights are validated by mutagenesis analyses of CopC-mediated ADPR de-acylization in vitro and animal infection in vivo. Our study offers a structural framework for understanding the molecular basis of arginine ADPR deacylization catalyzed by the CopC family.
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