Proteolysis and multimerization regulate signaling along the two-component regulatory system AdeRS

Zhenlin Ouyang; Fang Zheng; Li Zhu; Jan Felix; Di Wu; Ke Wu; Irina Gutsche; Yi Wu; Peter M Hwang; Junjun She; Yurong Wen

doi:10.1016/j.isci.2021.102476

Proteolysis and multimerization regulate signaling along the two-component regulatory system AdeRS

iScience. 2021 Apr 26;24(5):102476. doi: 10.1016/j.isci.2021.102476. eCollection 2021 May 21.

Authors

Zhenlin Ouyang¹, Fang Zheng², Li Zhu³, Jan Felix⁴, Di Wu³, Ke Wu³, Irina Gutsche⁴, Yi Wu², Peter M Hwang⁵, Junjun She¹, Yurong Wen^{1

2}

Affiliations

¹ Talent Highland and Center for Gut Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
² The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
³ MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China.
⁴ Institut de Biologie Structurale, Univ. Grenoble Alpes, CEA, CNRS, IBS, 71 avenue des Martyrs, Grenoble F-38044, France.
⁵ Departments of Medicine and Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.

Abstract

Bacterial two-component regulatory systems are ubiquitous environment-sensing signal transducers involved in pathogenesis and antibiotic resistance. The Acinetobacter baumannii two-component regulatory system AdeRS is made up of a sensor histidine kinase AdeS and a cognate response regulator AdeR, which together reduce repression of the multidrug-resistant efflux pump AdeABC. Herein we demonstrate that an N-terminal intrinsically disordered tail in AdeR is important for the upregulation of adeABC expression, although it greatly increases the susceptibility of AdeR to proteasome-mediated degradation. We also show that AdeS assembles into a hexameric state that is necessary for its full histidine kinase activity, which appears to occur via cis autophosphorylation. Taken together, this study demonstrates new structural mechanisms through which two-component systems can transduce environmental signals to impact gene expression and enlightens new potential antimicrobial approach by targeting two-component regulatory systems.

Keywords: Microbiology; Molecular Structure; Protein structure aspects.