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

• Published in: iScience 2021-05, Vol.24 (5), p.102476-102476, Article 102476
• Main Authors: Ouyang, Zhenlin, Zheng, Fang, Zhu, Li, Felix, Jan, Wu, Di, Wu, Ke, Gutsche, Irina, Wu, Yi, Hwang, Peter M., She, Junjun, Wen, Yurong
• Format: Article
• Language: English
• Subjects: Biochemistry, Molecular Biology; Life Sciences; Microbiology; Molecular Structure; Protein structure aspects; Structural Biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.102476

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. [Display omitted] •Crystal structure of AdeR dimer with traceable N-terminal intrinsically disordered region.•N-terminal intrinsically disordered region AdeR is involved in proteasome proteolysis.•Crystal structure of AdeS catalytic domain demonstrates cis autophosphorylation.•AdeS can assemble into hexamer and is crucial for its full kinase activity. Molecular Structure ; Microbiology; Protein structure aspects