Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus
Abstract
Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase ‘WalK’ (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus. Characterization of the crystal structure of erWalK revealed a canonical Per-Arnt-Sim (PAS) domain for signal sensing. Single amino-acid mutation of potential signal-transduction residues resulted in severely impaired function of WalKR. A small molecule derived from structure-based virtual screening against erWalK is capable of selectively activating the walKR TCS. Lastly, the molecular level characterization of erWalK will not only facilitate exploration of natural signal(s) but also provide a template for rational design of erWalK inhibitors.
- Authors:
-
- The Univ. of Chicago, Chicago, IL (United States)
- Chinese Academy of Sciences, Shanghai (China)
- Northwestern Univ., Argonne, IL (United States)
- Indiana Univ. School of Medicine-Northwest, Gary, IN (United States)
- Northwestern Univ., Evanston, IL (United States)
- Univ. of Chicago, Chicago, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1247346
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 7; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Ji, Quanjiang, Chen, Peter J., Qin, Guangrong, Deng, Xin, Hao, Ziyang, Wawrzak, Zdzislaw, Yeo, Won -Sik, Quang, Jenny Winjing, Cho, Hoonsik, Luo, Guan -Zheng, Weng, Xiaocheng, You, Qiancheng, Luan, Chi -Hao, Yang, Xiaojing, Bae, Taeok, Yu, Kunqian, Jiang, Hualiang, and He, Chuan. Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus. United States: N. p., 2016.
Web. doi:10.1038/ncomms11000.
Ji, Quanjiang, Chen, Peter J., Qin, Guangrong, Deng, Xin, Hao, Ziyang, Wawrzak, Zdzislaw, Yeo, Won -Sik, Quang, Jenny Winjing, Cho, Hoonsik, Luo, Guan -Zheng, Weng, Xiaocheng, You, Qiancheng, Luan, Chi -Hao, Yang, Xiaojing, Bae, Taeok, Yu, Kunqian, Jiang, Hualiang, & He, Chuan. Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus. United States. https://doi.org/10.1038/ncomms11000
Ji, Quanjiang, Chen, Peter J., Qin, Guangrong, Deng, Xin, Hao, Ziyang, Wawrzak, Zdzislaw, Yeo, Won -Sik, Quang, Jenny Winjing, Cho, Hoonsik, Luo, Guan -Zheng, Weng, Xiaocheng, You, Qiancheng, Luan, Chi -Hao, Yang, Xiaojing, Bae, Taeok, Yu, Kunqian, Jiang, Hualiang, and He, Chuan. Fri .
"Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus". United States. https://doi.org/10.1038/ncomms11000. https://www.osti.gov/servlets/purl/1247346.
@article{osti_1247346,
title = {Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus},
author = {Ji, Quanjiang and Chen, Peter J. and Qin, Guangrong and Deng, Xin and Hao, Ziyang and Wawrzak, Zdzislaw and Yeo, Won -Sik and Quang, Jenny Winjing and Cho, Hoonsik and Luo, Guan -Zheng and Weng, Xiaocheng and You, Qiancheng and Luan, Chi -Hao and Yang, Xiaojing and Bae, Taeok and Yu, Kunqian and Jiang, Hualiang and He, Chuan},
abstractNote = {Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase ‘WalK’ (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus. Characterization of the crystal structure of erWalK revealed a canonical Per-Arnt-Sim (PAS) domain for signal sensing. Single amino-acid mutation of potential signal-transduction residues resulted in severely impaired function of WalKR. A small molecule derived from structure-based virtual screening against erWalK is capable of selectively activating the walKR TCS. Lastly, the molecular level characterization of erWalK will not only facilitate exploration of natural signal(s) but also provide a template for rational design of erWalK inhibitors.},
doi = {10.1038/ncomms11000},
journal = {Nature Communications},
number = ,
volume = 7,
place = {United States},
year = {Fri Mar 18 00:00:00 EDT 2016},
month = {Fri Mar 18 00:00:00 EDT 2016}
}
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