Across evolution, cells adapt their proteome in response to internal and external signals. A simple model of such a process is provided by the heat-shock response in Gram-positive bacteria. In these species, sensing a temperature upshift results in the activation of the protein kinase McsB phosphorylating transcription factors that control expression of numerous genes.
McsB is of great interest for at least two reasons. First, it is the first kinase shown to phosphorylate proteins on arginine residues and, consistently, displays no homology to classical protein kinases, instead constituting a novel protein kinase class related to the eukaryotic metabolic enzyme creatine kinase. Second, as an efficient stress response is a prerequisite for a successful host invasion, McsB is important for virulence of notorious Gram-positive pathogens such as Staphylococcus aureus and may thus serve as a pharmacological target.
In order to investigate the unique function of McsB, we performed its structural and functional analysis. A series of X-ray structures of McsB reveals the molecular mechanism of protein arginine phosphorylation which is strikingly different from that of canonical protein kinases. Accompanying in vitro and in vivo functional studies of McsB shed further light on its mechanism and elucidate its biological role in coordinating the heat-shock response. Our work opens potential therapeutic avenues for combating antibiotic-resistant bacteria and poses an interesting question: whether arginine phosphorylation, a novel protein modification that has remained elusive until recently, is also present in eukaryotes.