phosphorylated protein has a relatively short lifetime. The protein is phosphorylated at an aspartate residue, a high-energy modification that has a half-life of several hours. The chemical stability of the aspartyl phosphate is often further reduced in these systems by both intrinsic autophosphatase activity within the response regulator and by auxiliary phosphatase proteins, resulting in half-lives that range from seconds to hours in different signaling systems.

Two-component systems are very widespread throughout the bacterial kingdom. In a typical genome there are about twenty to thirty of these regulatory systems that are involved in many different functions. Some of these are housekeeping functions, but in addition, these proteins are often involved in the regulation of expression of various types of toxins and virulence factors, and in mediating antibiotic resistance through a variety of different mechanisms. This regulation is important for host-pathogen interactions.

These proteins are present and abundant in bacteria and are present to a limited extent in some eukaryotic cells. They have been found in yeasts, and in the slime mold Dictyostelium. They are quite prevalent in plants, but they have not been identified in animals. And this, of course, makes them promising targets for the development of antimicrobial agents.

There are a very large number of these systems that have been identified. There are well over a thousand different two-component systems that have been found in a variety of bacterial genomes; not surprisingly, like components of any signal transduction system, these proteins are incredibly modular in nature. The conserved domains can be assembled in a variety of different ways into proteins, and the proteins can be assembled in a variety of ways into pathways, creating diverse and complex schemes.

In a typical system, consisting of just two components, the histidine kinase is a transmembrane protein with a variable extracellular sensing domain and a conserved intracellular kinase domain. Phosphoryl transfer occurs to the conserved domain of the response regulator that in turn, controls the activity of an associated variable effector domain. The response regulator protein is often a transcription factor that regulates expression of a specific group of genes.

In other systems, these components can be arrayed in a much more complex fashion with multiple kinases feeding into single response regulators, single kinases feeding into multiple-response regulators, and in many cases, multiple modules allowing for multiple transfers from histidine to aspartate residues in what are known as phospho-relay schemes.

In eukaryotic two-component systems, this kind of multiple phospho-relay is the norm rather than the exception and the phospho-relay systems



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