A toxin-deformation dependent inhibition mechanism in the T7SS toxin-antitoxin system of Gram-positive bacteria

Yongjin Wang, Yang Zhou, Chaowei Shi, Jiacong Liu, Guohua Lv, Huisi Huang, Shengrong Li, Liping Duan, Xinyi Zheng, Yue Liu, Haibo Zhou, Yonghua Wang, Zhengqiu Li, Ke Ding (), Pinghua Sun (), Yun Huang (), Xiaoyun Lu () and Zhi-Min Zhang ()
Additional contact information
Yongjin Wang: Jinan University
Yang Zhou: Jinan University
Chaowei Shi: University of Science and Technology of China
Jiacong Liu: Jinan University
Guohua Lv: Jinan University
Huisi Huang: Jinan University
Shengrong Li: Jinan University
Liping Duan: Jinan University
Xinyi Zheng: Jinan University
Yue Liu: Jinan University
Haibo Zhou: Jinan University
Yonghua Wang: South China University of Technology
Zhengqiu Li: Jinan University
Ke Ding: Jinan University
Pinghua Sun: Jinan University
Yun Huang: Weill Cornell Medicine
Xiaoyun Lu: Jinan University
Zhi-Min Zhang: Jinan University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Toxin EsaD secreted by some S. aureus strains through the type VII secretion system (T7SS) specifically kills those strains lacking the antitoxin EsaG. Here we report the structures of EsaG, the nuclease domain of EsaD and their complex, which together reveal an inhibition mechanism that relies on significant conformational change of the toxin. To inhibit EsaD, EsaG breaks the nuclease domain of EsaD protein into two independent fragments that, in turn, sandwich EsaG. The originally well-folded ββα-metal finger connecting the two fragments is stretched to become a disordered loop, leading to disruption of the catalytic site of EsaD and loss of nuclease activity. This mechanism is distinct from that of the other Type II toxin-antitoxin systems, which utilize an intrinsically disordered region on the antitoxins to cover the active site of the toxins. This study paves the way for developing therapeutic approaches targeting this antagonism.

Date: 2022
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DOI: 10.1038/s41467-022-34034-w

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