Keeping signals straight in phosphorelay signal transduction.

Bacteria are highly adaptable organisms capable of growth on countless carbon and nitrogen sources and of occupying an inexhaustible variety of ecological niches. Any particular bacterium possesses a subset of these capabilities that are encoded by a repertoire of genes normally kept unexpressed unless called upon. The key to adaptability in bacteria is their capacity to express only those genes for enzymes and pathways that they need for maximal growth in the environment in which they find themselves. This is achieved by their ability to recognize the composition of their environment by sensing signals emanating from it. One of the major mechanisms of signal recognition leading to specific gene expression is the two-component system and its more-complex variant, the phosphorelay (Fig. 1). Two-component systems consist of a signal recognition sensor kinase that autophosphorylates on a histidine, usually in response to the presence of a signal, and a response regulator transcription factor that activates or represses gene expression when phosphorylated by the sensor kinase to which it is mated. Thus, sensor kinases and response regulators come in pairs; the sensor kinase detects signals and the response regulator carries out the action that the presence of the signal engenders. Two-component systems have the ability to transfer information from one cellular location to another. The sensor kinases are mainly integral membrane proteins, perhaps because most are responsive to external signals and the genes that need to be activated are somewhere else that only the cytoplasmic response regulator can access. This information transfer from one location to another requires specific recognition between the interacting components, and it is recognition that represents the potential Achilles heel in the signaling system. Erroneous recognition between an activated sensor kinase and inappropriate response regulators would lead to regulation of the wrong genes. That signal propagation in two-component pathways requires precise interaction between phosphoryl donors and acceptors to ensure the correct response does not require profound insight. However, it is not a trivial matter either. Bacteria such as Escherichia coli, Bacillus subtilis, and Synchocystis species with sizeable genomes and, therefore, a large repertoire of genes for adaptability possess 30 to 40 different pairs of two-component systems, each dedicated to unique signals and genes (4, 7, 8). Even more amazing is Nostoc punctiformis with 145 sensor kinases and 103 response regulators identified in a partially sequenced genome (www.jgi.doe.gov). Progenitors of these bacteria adopted the two-component system as a useful and precise system of regulation and expanded it by gene duplication and mutation to serve a wide variety of purposes from gene regulation to chemotaxis. Bioinformatic studies comparing the sensor kinases and response regulators clearly show the presence of two major and several minor families of two-component systems within each bacterium that retain high amino acid identity and similarity within the family (4, 7). Yet these highly similar systems must process different signals, interact only with their partner, and activate unique genes. The question arises, how is fidelity achieved in such signal transduction systems? How do newly duplicated two-component systems evolve specificity?