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 Scopus citations

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

ASJC Scopus subject areas

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

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    Ji, Q., Chen, P. J., Qin, G., Deng, X., Hao, Z., Wawrzak, Z., Yeo, W. S., Quang, J. W., Cho, H., Luo, G. Z., Weng, X., You, Q., Luan, C. H., 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, 7, [11000]. https://doi.org/10.1038/ncomms11000