Structure and Function of the Protein Arginine Kinase McsB

Abstract

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. Importantly, the temperature‐induced adaptation at the transcriptional level is preceded and indeed caused by post‐transcriptional modifications of the existing protein pool. The central player here is the protein kinase McsB that is known to phosphorylate and regulate certain heat‐shock transcription factors.McsB is of great interest for at least two reasons. First, McsB is the only protein kinase shown to phosphorylate arginine residues and, consistently, displays no homology to classic protein kinases. Second, owing to its importance for the virulence of notorious Gram‐positive pathogens such as Staphylococcus aureus and given its unique protein kinase mechanism, McsB represents a promising pharmacological target.In order to investigate the function of McsB, we determined a series of X‐ray structures revealing the molecular mechanism of protein arginine phosphorylation in great detail. This mechanism is not only strikingly different from that of canonical protein kinases, but also is under control of an allosteric coupling between the two protomers of the McsB dimer, as phosphoryl‐transfer at one subunit triggers the product release at the other. Accompanying in vitro and in vivo functional studies of McsB shed further light on its mechanism and elucidate its biological role in coordinating the bacterial heat‐shock response.