Cell-surface receptors and kinase regulation

In the bacterial chemosensory pathway, all of the cytoplasmic components assemble onto an lattice of transmembrane chemoreceptors to generate an ultrastable, ultrasensitive signaling array. This array is one of the simplest, yet highly efficient, biological integrated circuits.

The Falke group is currently investigating the molecular mechanisms of on-off switching of components within the chemosensory array, especially the mechanisms by which transmembrane receptors bind specific attractants and regulate the output kinase activity. This kinase activity controls the swimming motor and cellular migration up attractant gradients. The known structures of the pathway components greatly facilitate molecular analysis of their on-off switching mechanisms.

The group is developing an array of biochemical, chemical and spectroscopic approaches capable of analyzing structural dynamics during on-off switching in the functional, membrane-bound, signaling array. Specific goals include elucidation of the mechanisms by which attractant and adaptation signals are transmitted through the transmembrane receptors to the kinase, and how these receptor on-off signals switch the kinase on and off. The resulting molecular mechanisms are likely conserved throughout the diverse family of 2-component pathways, which control most cellular processes in bacteria. Such broad relevance ensures that mechanistic advances will have significant impacts on the field of signaling biology, as well as on the development of new classes of (i) broad-spectrum antibiotics, (ii) chemotaxis inhibitors that block wound seeking and infection, and (iii) ultrasensitive, ultrastable biosensors. Moreover, many of the tools developed in this simple, bacterial system can ultimately be applied to eukaryotic systems.