Most prokaryotic signal-transduction systems and a few eukaryotic pathways use phosphotransfer schemes involving two conserved components, a histidine protein kinase (HK) and a response regulator protein (RR) (see <PDOC50110>). The HK, which is regulated by environmental stimuli, autophosphorylates at a histidine residue, creating a high-energy phosphoryl group that is subsequently transferred to an aspartate residue in the RR domain. Phosphorylation induces a conformational change in RR that results in activation of an associated domain that effects the response.

Both prokaryotic and eukaryotic HKs contain the same basic signaling components, namely a diverse sensing domain and a highly conserved kinase core that has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily. The overall activity of the kinase is modulated by input signals to the sensing domain. HKs undergo an ATP-dependent autophosphorylation at a conserved His residue in the kinase core. Autophosphorylation is a bimolecular reaction between homodimers, in which one HK monomer catalyzes the phosphorylation of the conserved His residue in the second monomer.

The sensing domains are variable in sequence, reflective of the many different environmental signals to which HKs are responsive, whereas the about 250-residue kinase core is more conserved. The kinase core is composed of a dimerization domain and an ATP/ADP-binding phosphotransfer or catalytic domain and can be identified by five conserved primary sequence motifs present in both eukaryotic and procaryotic HKs. These motifs have been termed the H, N, G1, F and G2 boxes. The conserved His substrate is the central feature in the H box, whereas the N, G1, F and G2 boxes define the nucleotide binding cleft. In most HKs, the H box is part of the dimerization domain. However, for some proteins, like CheA, the conserved His is located at the far N-terminus of the protein in a separate HPt domain. The N, G1, F and G2 boxes are usually contiguous, but the spacing between these motifs is somewhat varied. The catalytic core forms an α-β sandwich consisting of five antiparallel β strands and three α helices (see <PDB:1BXD>) [1,2,3].

The profile we developed covers the histidine kinase core.