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Crystal structure of the extracellular receptor domain of the essential sensor kinase WalK from Staphylococcus aureus
Structural highlights
FunctionWALK_STAAE Member of the two-component regulatory system WalK/WalR that regulates genes involved in cell wall metabolism, virulence regulation, biofilm production, oxidative stress resistance and antibiotic resistance via direct or indirect regulation of autolysins. Functions as a sensor protein kinase which is autophosphorylated at a histidine residue in the dimerization domain and transfers its phosphate group to the conserved aspartic acid residue in the regulatory domain of WalR. In turn, WalR binds to the upstream promoter regions of the target genes to positively and negatively regulate their expression.[UniProtKB:Q9RDT3] Publication Abstract from PubMedMost 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. Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus.,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 Nat Commun. 2016 Mar 18;7:11000. doi: 10.1038/ncomms11000. PMID:26987594[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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