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Scientists Decode and Rewire Bacterial Communication Pathways

NEW YORK (GenomeWeb News) – A team of scientists has worked out the mechanisms that confer specificity when bacteria decipher and communicate messages from the outside world — and has found a way to start rewiring these pathways.
In a paper appearing online in Cell today, researchers from the Massachusetts Institute of Technology and the University of Pennsylvania looked for telltale amino acid changes in communication proteins from almost 200 bacterial genomes. In doing so, they not only determined how the communication networks maintain specificity, but also found a way to circumvent some pathways and, instead, activate others. That approach, they suggest, could bolster the use of genetically engineered bacteria in synthetic signaling circuits.
In general, bacteria identify and react to signals in the outside world using what’s called a two-component transduction system. In this system, a group of proteins called histidine kinases receives signals from the environment and activates another set of proteins called response regulators, which then pass on the signal.
But various histidine kinases tend to closely resemble one another, as do different response regulators. That raises questions about how members of kinase-regulator pairs recognize one another without accidentally activating the wrong pathway. And to date no one has come up with the sort of high-resolution protein structure of interacting pairs that would reveal such substrate specificity.
For this paper, the team, led by MIT biologist Michael Laub, decided to take another tack. They looked for signaling specificity using amino acid covariation analysis. Because mutations that change a histidine kinase’s interactions likely coincide with corresponding changes in its response receptor, the team speculated that looking for amino acid variation would reveal residues involved in signaling specificity.
“As specificity in two-component signaling systems relies on the precise molecular recognition between cognate pairs, a set of amino acids must exist that confers specificity on the interaction,” Laub and his team wrote.
Since kinase-regulator pairs are typically encoded on the same operon, the researchers were able to treat each pair as one sequence, aligning it against similar pairs in almost 200 bacterial genomes. Based on their analysis of roughly 1,300 kinase-regulator pairs, Laub and his colleagues were able to predict which part of the histidine kinase mediates its specificity.
They found that by swapping out histidine kinase domains, they could actually switch the signaling pathways activated by a kinase — a result they verified in Escherichia coli cells using fluorescent proteins as reporters.
That opens up new possibilities for engineering bacteria that respond in specific ways to specific stimuli. For instance, in a statement issued today, Laub suggested that this type of tinkering could one day let scientists create bio-indicator bacteria that glow when exposed to defined pollutants.
Still, the team noted, for future studies having information about histidine kinase structures will likely supplement information gleaned from the type of covariation analysis used here.
“[W]e anticipate that a similar, rational rewiring of other histidine kinases will be possible by using the design approach developed here,” the authors wrote, adding, “Our results demonstrate that the analysis of amino acid covariation in large, multiple sequence alignments can effectively guide the identification of specificity determinants in protein-protein interactions.”

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