Two-component signal transduction (TCST) systems are the principal means fo
r coordinating responses to environmental changes in bacteria as well as so
me plants, fungi, protozoa, and archaea. These systems typically consist of
a receptor histidine kinase, which reacts to an extracellular signal by ph
osphorylating a cytoplasmic response regulator, causing a change in cellula
r behavior. Although several model systems, including sporulation and chemo
taxis, have been extensively studied, the evolutionary relationships betwee
n specific TCST systems are not well understood, and the ancestry of the si
gnal transduction components is unclear. Phylogenetic trees of TCST compone
nts from 14 complete and 6 partial genomes, containing 183 histidine kinase
s and 220 response regulators, were constructed using distance methods. The
trees showed extensive congruence in the positions of 11 recognizable phyl
ogenetic clusters. Eukaryotic sequences were found almost exclusively in on
e cluster, which also showed the greatest extent of domain variability in i
ts component proteins, and archaeal sequences mainly formed species-specifi
c clusters. Three clusters in different parts of the kinase tree contained
proteins with serine-phosphorylating activity. All kinases were found to be
monophyletic with respect to other members of their superfamily, such as t
ype Il topoisomerases and Hsp90. Structural analysis further revealed signi
ficant similarity to the ATP-binding domain of eukaryotic protein kinases.
TCST systems are of bacterial origin and radiated into archaea and eukaryot
es by lateral gene transfer. Their components show extensive coevolution, s
uggesting that recombination has not been a major factor in their different
iation. Although histidine kinase activity is prevalent, serine kinases hav
e evolved multiple times independently within this family, accompanied by a
loss of the cognate response regulator(s). The structural and functional s
imilarity between TCST kinases and eukaryotic protein kinases raises the po
ssibility of a distant evolutionary relationship.