These proteins possess a phosphorylatable histidine residue and are responsible for transferring a phosphoryl group from an aspartate residue on an intermediate "receiver" domain, typically part of a hybrid histidine kinase, to an aspartate on a final response regulator.

[4] The increased complexity of the phosphorelay system compared to orthodox two-component signaling provides additional opportunities for regulation and improves the specificity of the response.

[8] In some known cases, there is an additional form of regulation in phosphohistidine phosphatase enzymes that act on HPt, such as the Escherichia coli protein SixA which targets ArcB.

[2] The monomeric and dimeric forms do not have detectable sequence similarity and are most likely not evolutionarily related; they are instead examples of convergent evolution.

Relative to the number of histidine kinase and response regulators present in a genome, eukaryotes have more identifiable HPt domains than bacteria.