Protein Connectivity in Chemotaxis Receptor Complexes

The chemotaxis sensory system allows bacteria such as Escherichia coli to swim towards nutrients and away from repellents. The underlying pathway is remarkably sensitive in detecting chemical gradients over a wide range of ambient concentrations. Interactions among receptors, which are predominantly clustered at the cell poles, are crucial to this sensitivity. Although it has been suggested that the kinase CheA and the adapter protein CheW are integral for receptor connectivity, the exact coupling mechanism remains unclear. Here, we present a statistical-mechanics approach to model the receptor linkage mechanism itself, building on nanodisc and electron cryotomography experiments. Specifically, we investigate how the sensing behavior of mixed receptor clusters is affected by variations in the expression levels of CheA and CheW at a constant receptor density in the membrane. Our model compares favorably with dose-response curves from in vivo Förster resonance energy transfer (FRET) measurements, demonstrating that the receptor-methylation level has only minor effects on receptor cooperativity. Importantly, our model provides an explanation for the non-intuitive conclusion that the receptor cooperativity decreases with increasing levels of CheA, a core signaling protein associated with the receptors, whereas the receptor cooperativity increases with increasing levels of CheW, a key adapter protein. Finally, we propose an evolutionary advantage as explanation for the recently suggested CheW-only linker structures.Author Summary: Receptor clusters of the bacterial chemotaxis sensory system act as antennae to amplify tiny changes in concentrations in the chemical environment of the cell, ultimately steering the cell towards nutrients and away from toxins. Despite bacterial chemotaxis being the most widely studied sensory pathway, the exact architecture of the receptor clusters remains speculative, with understanding suffering from a number of paradoxical observations. To address these issues with respect to the protein arrangement in the linkers connecting receptors, we present a statistical-mechanics model that combines insights from electron cryotomography on the linker architecture with results from fluorescence imaging of signaling in living cells. Although the signaling data for different expression levels of key molecular components in the linkers seems contradictory at first, our model reconciles these predictions with structural and biochemical data. Finally, we provide an evolutionary explanation for the observation that some of the incorporated linkers do not seem to transmit signals from the receptors.