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.
Highlights
Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis
Signal transduction mediated by two-component systems (TCSs) is one of the primary strategies utilized by bacteria for adapting to changing environments
The sensor kinase of this TCS in S. aureus, WalK, possesses three functional domains including the intracellular kinase, the transmembrane helices as well as the extracellular receptor domain, the first two of which have been found to be conserved across the bacteria that contain this TCS
Summary
Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. 3) in large part because of the emergence of drug-resistant strains, such as methicillin-resistant and vancomycin-resistant S. aureus[4] Besides antibiotic resistance, this human pathogen causes infections almost everywhere in the human body, resulting in a variety of diseases ranging from minor skin infections to life-threatening diseases[5,6]. This human pathogen causes infections almost everywhere in the human body, resulting in a variety of diseases ranging from minor skin infections to life-threatening diseases[5,6] The versatility of this bacterium in pathogenesis is largely attributed to its capacity to coordinately express virulence factors according to changing environmental stimulus, mediated predominantly by its 16 TCSs (for example, agrAC, saeRS and arlRS) as well as key virulence regulators (for example, sarA, mgrA and cymR)[7,8,9,10,11,12]. We discovered a small molecule, which activates WalKR TCS via targeting erWalK, demonstrating the feasibility of this strategy
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