Receiver domain structure and function in response regulator proteins

Abstract

During signal transduction by two-component regulatory systems, sensor kinases detect and encode input information while response regulators (RRs) control output. Most receiver domains function as phosphorylation-mediated switches within RRs, but some transfer phosphoryl groups in multistep phosphorelays. Conserved features of receiver domain amino acid sequence correlate with structure and hence function. Receiver domains catalyze their own phosphorylation and dephosphorylation in reactions requiring a divalent cation. Molecular dynamics simulations are supplementing structural investigation of the conformational changes that underlie receiver domain switch function. As understanding of features shared by all receiver domains matures, factors conferring differences (e.g. in reaction rate or specificity) are receiving increased attention. Numerous examples of atypical receiver or pseudo-receiver domains that function without phosphorylation have recently been characterized.

Figure 1

Schematic diagram of the relationship between receiver domain amino acid sequence and basic structural elements as described in the text, with the active site viewed from the (a) side or (b) top. Five α-helices surround a parallel five-stranded β-sheet. Loops connecting strands and helices are shown as black solid lines on the active site side of the domain and gray dashed lines on the opposite side, with arrowheads indicating N- to C-terminal direction. Orange indicates pattern of conserved hydrophobic residues on the central β-strands and faces of three α-helices. The highly conserved residues of the active site quintet are in blue, with the moderately conserved aromatic residue in cyan. Divalent metal ion is magenta. Residues presumed to be strongly conserved for structural reasons are in gray. Frequently conserved acidic residues of unknown function are in yellow.

Figure 1

Schematic diagram of the relationship between receiver domain amino acid sequence and basic structural elements as described in the text, with the active site viewed from the (a) side or (b) top. Five α-helices surround a parallel five-stranded β-sheet. Loops connecting strands and helices are shown as black solid lines on the active site side of the domain and gray dashed lines on the opposite side, with arrowheads indicating N- to C-terminal direction. Orange indicates pattern of conserved hydrophobic residues on the central β-strands and faces of three α-helices. The highly conserved residues of the active site quintet are in blue, with the moderately conserved aromatic residue in cyan. Divalent metal ion is magenta. Residues presumed to be strongly conserved for structural reasons are in gray. Frequently conserved acidic residues of unknown function are in yellow.

Figure 2

Schematic diagram indicating key differences between (a) inactive and (b) active conformations. View and color coding as in Figure 1b, with some features removed for clarity. Residues and loops that undergo the most significant changes are shown in red (inactive) or dark green (active). Phosphoryl group and lines indicating key hydrogen bonds are in light green.

Figure 2

Schematic diagram indicating key differences between (a) inactive and (b) active conformations. View and color coding as in Figure 1b, with some features removed for clarity. Residues and loops that undergo the most significant changes are shown in red (inactive) or dark green (active). Phosphoryl group and lines indicating key hydrogen bonds are in light green.

Figure 3

Variable active site residues affect autodephosphorylation kinetics. View and color coding as in Figure 2b. The amino acids located one and two positions to the C-terminal sides of the Asp phosphorylation site and the highly conserved Thr/Ser are shown in brown. Established and putative roles are described in the text.