Structural insights into caspase ADPR deacylization catalyzed by a bacterial effector and host calmodulin

Zhang, Kuo1,2; Peng, Ting2,3,4,5,6; Tao, Xinyuan2,3,4,5,6; Tian, Miao1,2; Li, Yanxin3,4,5,6; Wang, Zhao1; Ma, Shuaifei3,4,5,6; Hu, Shufan2,3,4,5,6; Pan, Xing2,3,4; Xue, Juan2,3,4; Luo, Jiwei3,4; Wu, Qiulan1; Fu, Yang1; Li, Shan2,3,4,5

2022-12-15

10.1016/j.molcel.2022.10.032

MOLECULAR CELL   Impact Factor & Quartile

1097-2765

1097-4164

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.

SCI

English

NI Journal Papers

First ; Corresponding

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]

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:000919685300002

CELL PRESS

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Southern Univ Sci & Technol, Sch Med, Shenzhen 518055, Guangdong, Peoples R China
2.Hubei Univ Med, Taihe Hosp, Inst Infect & Immun, Shiyan 442000, Hubei, Peoples R China
3.Huazhong Agr Univ, Coll Life Sci & Technol, Wuhan 430070, Hubei, Peoples R China
4.Huazhong Agr Univ, Coll Biomed & Hlth, Wuhan 430070, Hubei, Peoples R China
5.Huazhong Agr Univ, Shenzhen Inst Nutr & Hlth, Wuhan 430070, Hubei, Peoples R China
6.Chinese Acad Agr Sci, Agr Genom Inst Shenzhen, Shenzhen 518055, Guangdong, Peoples R China

Zhang, Kuo,Peng, Ting,Tao, Xinyuan,et al. Structural insights into caspase ADPR deacylization catalyzed by a bacterial effector and host calmodulin[J]. MOLECULAR CELL,2022,82(24).

Zhang, Kuo.,Peng, Ting.,Tao, Xinyuan.,Tian, Miao.,Li, Yanxin.,...&Li, Shan.(2022).Structural insights into caspase ADPR deacylization catalyzed by a bacterial effector and host calmodulin.MOLECULAR CELL,82(24).

Zhang, Kuo,et al."Structural insights into caspase ADPR deacylization catalyzed by a bacterial effector and host calmodulin".MOLECULAR CELL 82.24(2022).