  In many sensory systems, transmembrane receptors are spatially organized in
large clusters. Such arrangement may facilitate signal amplification and the
integration of multiple stimuli. However, this organization likely also affects
the kinetics of signaling since the cytoplasmic enzymes that modulate the
activity of the receptors must localize to the cluster prior to receptor
modification. Here we examine how these spatial considerations shape signaling
dynamics at rest and in response to stimuli. As a model, we use the chemotaxis
pathway of Escherichia coli, a canonical system for the study of how organisms
sense, respond, and adapt to environmental stimuli. In bacterial chemotaxis,
adaptation is mediated by two enzymes that localize to the clustered receptors
and modulate their activity through methylation-demethylation. Using a novel
stochastic simulation, we show that distributive receptor methylation is
necessary for successful adaptation to stimulus and also leads to large
fluctuations in receptor activity in the steady state. These fluctuations arise
from noise in the number of localized enzymes combined with saturated
modification kinetics between localized enzymes and receptor substrate. An
analytical model explains how saturated enzyme kinetics and large fluctuations
can coexist with an adapted state robust to variation in the expression level
of the pathway constituents, a key requirement to ensure the functionality of
individual cells within a population. This contrasts with the well-mixed
covalent modification system studied by Goldbeter and Koshland in which mean
activity becomes ultrasensitive to protein abundances when the enzymes operate
at saturation. Large fluctuations in receptor activity have been quantified
experimentally. Here we clarify their mechanistic relationship with
well-studied aspects of the chemotaxis system, precise adaptation and
functional robustness.
