A New Perspective on Response Regulator Activation

Abstract

Two-component signaling pathways are the most prevalent of strategies used by bacteria for coupling environmental signals to adaptive responses (10). The response regulator component typically functions at the end of the pathway, with the conserved regulatory/receiver domain acting as a phosphorylation-activated switch to control an associated or attached effector domain that elicits the output response (24). In the simplest mechanistic model, these domains are considered to exist in two conformations, an inactive (“off”) state and an active (“on”) state, with phosphorylation at a conserved active-site aspartic acid residue serving to shift the equilibrium toward the active state (22). In this issue of the Journal of Bacteriology, Dyer and Dahlquist provide direct structural evidence that this model is overly simplistic (8). Their crystallographic characterization of the unphosphorylated Escherichia coli chemotaxis response regulator CheY bound to a peptide of its effector protein target, the flagellar switch protein FliM, reveals a conformation that is intermediate between inactive and active states. This finding provides evidence against a strict two-state mechanism in which the orientations of key residues that distinguish the inactive and active states are presumed to be obligatorily coupled. The intermediate state reported in their study not only provides insight into the mechanism of switching between inactive and active states but also has potential physiological relevance for some response regulators.