A clarifying perspective on bacterial pseudo-receiver domains

Two-component regulatory systems typically consist of a sensor kinase and a response regulator. Phosphorylation of the receiver domain controls response regulator activity. Pseudo-receivers (PsRs) are identified computationally as receivers but lack key residues to catalyze phosphotransfer reactions. Although PsRs are common, molecular mechanisms that activate and inactivate bacterial PsRs remain a mystery. We untangled four potentially related but distinct concepts: bacterial PsRs, receivers with regulatory mechanisms in addition to phosphorylation, receivers that are active without phosphorylation, and orphan receivers without an obvious partner sensor kinase. We also analyzed bacterial PsR sequences and structures to identify regions of likely functional significance.