Abstract
Many regulatory and signaling proteins have multiple modification sites. In bacterial chemotaxis, each chemoreceptor has multiple methylation sites that are responsible for adaptation. However, whether the ordering of the multisite methylation process affects adaptation remains unclear. Furthermore, the benefit of having multiple modification sites is also unclear. Here, we show that sequentially ordered methylation/demethylation is critical for perfect adaptation; adaptation accuracy decreases as randomness in the multisite methylation process increases. A tradeoff between adaptation accuracy and response gain is discovered. We find that this accuracy-gain tradeoff is lifted significantly by having more methylation sites, but only when the multisite modification process is sequential. Our study suggests that having multiple modification sites and a sequential modification process constitute a general strategy to achieve both accurate adaptation and high response gain simultaneously. Our theory agrees with existing data and predictions are made to help identify the molecular mechanism underlying ordered covalent modifications.
Highlights
Many regulatory and signaling proteins have multiple modification sites
How do different methylation kinetics, random or sequential, affect adaptation accuracy and response gain? What are the benefits to have multiple modification sites? In this paper, we address these questions by systematically investigating effects of different multisite modification processes, from purely random to strictly sequential, on system-level functions such as adaptation accuracy and signal amplification
Why are there multiple modification sites in a regulatory protein or a receptor? How is the performance of the system enhanced by having multiple modification sites? Here, we investigate how having multiple modification sites affects the gain Γ and accuracy ξ−1 for different modification dynamics
Summary
Many regulatory and signaling proteins have multiple modification sites. In bacterial chemotaxis, each chemoreceptor has multiple methylation sites that are responsible for adaptation. Adaptation in bacterial chemotaxis is achieved by a feedback mechanism in which the receptor methylation level (internal state of the receptor) is controlled by a methyltransferase CheR and a methylesterase CheB that act at a time scale much longer than the response time to a change in external stimulus (ligand concentration). Despite the general consensus on the importance of a negative feedback mechanism for accurate adaptation in bacterial chemotaxis, the detailed receptor methylation/demethylation kinetics among the multiple methylation sites remain unclear. We address these questions by systematically investigating effects of different multisite modification processes, from purely random to strictly sequential, on system-level functions such as adaptation accuracy and signal amplification. Our study leads to specific suggestions of future experiments to determine the molecular mechanism controlling the multisite modification dynamics
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