Structural highlights
Publication Abstract from PubMedThe KdpDE two-component system (TCS) regulates potassium homeostasis and virulence in various bacterial species. The KdpD histidine kinases of this system contain a universal stress protein (USP) domain which binds to the second messenger cyclic-di-adenosine monophosphate (c-di-AMP) for regulating transcriptional output from this TCS in Firmicutes such as Staphylococcus aureus. However, the structural basis of c-di-AMP specificity within the KdpD-USP domain is not well understood. Here, we resolved a 2.3 A crystal structure of the Staphylococcus aureus KdpD-USP domain (USPSa) complexed with c-di-AMP. Binding affinity analyses of USPSa mutants targeting the observed USPSa:c-di-AMP structural interface enabled the identification of the sequence residues that are required for c-di-AMP specificity. Based on the conservation of these residues in other Firmicutes, we identified the binding motif - (A/G/C)XSXSX2N(Y/F), which allowed us to predict c-di-AMP binding in other KdpD histidine kinases. Furthermore, we found that the USPSa domain contains structural features distinct from the canonical standalone USPs that bind ATP as a preferred ligand. These features include inward-facing conformations of its beta1-alpha1 and beta4-alpha4 loops, a short alpha2 helix, the absence of a triphosphate-binding Walker motif, and a unique dual phospho-ligand binding mode. It is therefore likely that USPSa-like domains in KdpD histidine kinases represent a novel subfamily of the USPs. Structural basis of KdpD histidine kinase binding to the second messenger c-di-AMP.,Dutta A, Batish M, Parashar V J Biol Chem. 2021 May 11:100771. doi: 10.1016/j.jbc.2021.100771. PMID:33989637[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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