Book of Abstracts: Albany 2005
Fidelity in Bacterial Signal Transduction
Bacteria possess the capability to adapt to fluctuating environments that may turn hostile unexpectedly. They do so by monitoring the environmental signals and expressing pathways needed for maximal growth under the new conditions. One of the major regulatory mechanisms for signal recognition and response is the two-component system and its more sophisticated variant, the phosphorelay. Two-component systems consist of a sensor histidine kinase and a response regulator. Signal input activates an ATP-dependent autophosphorylation of a histidine residue of a kinase and signal propagation in these systems involves phosphotransfer to an Asp residue of the response regulator. Most of the response regulators are transcription factors and they consist of two domains. The N-terminal domain receives the phosphoryl group from the kinase and regulates the DNA binding activity of the C-terminal effector domain. We had been studying the phosphorelay that controls the initiation of sporulation in Bacillus subtilis which is an expanded version of the two-component system consisting of four main components -- the histidine kinase KinA, the secondary messenger Spo0F, the phosphotransferase Spo0B, and the transcription factor Spo0A. We have elucidated the crystal structures of Spo0F, Spo0B, the molecular complex of Spo0F with Spo0B, and the DNA complex of Spo0A. Bacillus subtilis cells possess 34 two-component pairs each dedicated to unique signals and unique responses. Some species have even more than a hundred pairs. Hence, it is intriguing how a particular kinase specifically recognizes its partner and activates it to produce the correct response when there are such a large number of pairs with considerable similarities. Specificity can be generated through variations in shape and sequence in the response regulator making the concomitant changes in the phosphotransferase domain to maintain complementarity. The receiver domains of the response regulators are structurally very similar and have identical active sites lined by invariant catalytic residues. The four-helix bundle of Spo0B that mediates most of the interactions with Spo0F should be a prototype for the phosphotransferase domains of the majority of histidine kinases. The critical question of how a component of a signal transduction system specifically associates with its partner to produce the ideal environment for phosphotransfer will be addressed in the light of the structure of the Spo0F:Spo0B complex and computational analysis.
Kottayil I. Varughese
Division of Cellular Biology