Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

Quanjiang Ji, Peter J. Chen, Guangrong Qin, Xin Deng, Ziyang Hao, Zdzislaw Wawrzak, Won Sik Yeo, Jenny Winjing Quang, Hoonsik Cho, Guan Zheng Luo, Xiaocheng Weng, Qiancheng You, Chi Hao Luan, Xiaojing Yang, Taeok Bae, Kunqian Yu, Hualiang Jiang, Chuan He

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Article number11000
JournalNature Communications
Volume7
DOIs
StatePublished - Mar 18 2016

Fingerprint

Signal transduction
staphylococcus
Staphylococcus aureus
Signal Transduction
Phosphotransferases
homeostasis
hubs
Gram-Positive Bacteria
mutations
inhibitors
Cell Wall
bacteria
amino acids
Bacteria
Screening
Homeostasis
templates
screening
Crystal structure
Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus. / 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.

In: Nature Communications, Vol. 7, 11000, 18.03.2016.

Research output: Contribution to journalArticle

Ji, Q, Chen, PJ, Qin, G, Deng, X, Hao, Z, Wawrzak, Z, Yeo, WS, Quang, JW, Cho, H, Luo, GZ, Weng, X, You, Q, Luan, CH, Yang, X, Bae, T, Yu, K, Jiang, H & He, C 2016, 'Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus', Nature Communications, vol. 7, 11000. 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 ; He, Chuan. / Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus. In: Nature Communications. 2016 ; Vol. 7.
@article{54275429a29d436bbfaccb12b6d47efd,
title = "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. 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.",
author = "Quanjiang Ji and Chen, {Peter J.} and Guangrong Qin and Xin Deng and Ziyang Hao and Zdzislaw Wawrzak and Yeo, {Won Sik} and Quang, {Jenny Winjing} and Hoonsik Cho and Luo, {Guan Zheng} and Xiaocheng Weng and Qiancheng You and Luan, {Chi Hao} and Xiaojing Yang and Taeok Bae and Kunqian Yu and Hualiang Jiang and Chuan He",
year = "2016",
month = "3",
day = "18",
doi = "10.1038/ncomms11000",
language = "English (US)",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

AU - Ji, Quanjiang

AU - Chen, Peter J.

AU - Qin, Guangrong

AU - Deng, Xin

AU - Hao, Ziyang

AU - Wawrzak, Zdzislaw

AU - Yeo, Won Sik

AU - Quang, Jenny Winjing

AU - Cho, Hoonsik

AU - Luo, Guan Zheng

AU - Weng, Xiaocheng

AU - You, Qiancheng

AU - Luan, Chi Hao

AU - Yang, Xiaojing

AU - Bae, Taeok

AU - Yu, Kunqian

AU - Jiang, Hualiang

AU - He, Chuan

PY - 2016/3/18

Y1 - 2016/3/18

N2 - 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. 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.

AB - 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. 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.

UR - http://www.scopus.com/inward/record.url?scp=84961644395&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961644395&partnerID=8YFLogxK

U2 - 10.1038/ncomms11000

DO - 10.1038/ncomms11000

M3 - Article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11000

ER -