Electrostatics Facilitates the Trimer-of-Dimers Formation of the Chemoreceptor Signaling Domain

Abstract

Chemoreceptors are crucial components of the bacterial sensory system that modulates cellular motility. They detect changes in the environment and transmit information to CheA histidine kinase, which ultimately controls cellular flagellar motors. The prototypical Tsr chemoreceptor in E. coli is a homodimer containing two principle functional modules: (i) a periplasmic ligand-binding domain and (ii) a cytoplasmic signaling domain comprising an antiparallel, four-helix coiled-coil bundle. Receptor dimers are arranged into a trimer-of-dimers, which is a minimal physical unit essential for enhancing the CheA activity several hundredfold. Recent advances in cryo-electron tomography showed that trimers-of-dimers are arranged into highly ordered hexagon arrays at the cell pole; however, the mechanism underlying the trimer-of-dimer and higher order array formation remains unknown. Current evidence from structural and biochemical studies suggest that trimers-of-dimers are maintained exclusively by contacts at the chemoreceptor cytoplasmic tip. Here, using all-atom, microsecond-range MD simulation of the Tsr trimer-of-dimers crystal structure, we show that dimers within the trimer may interact throughout the entire length of the signaling domain. While inter-dimer contacts at the chemoreceptor tip occur via hydrophobic interactions, complete dimer "zipping" is facilitated by electrostatics, especially by the polar solvation component. We also show that many of the residues involved in establishing hydrogen bonds and salt bridges between dimers are evolutionary conserved.

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