期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：22
页码：10032-10037
DOI：10.1073/pnas.0913815107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：We used a model system of purified components to explore the effects of a downstream target on the signaling properties of a covalent modification cycle, an example of retroactivity. In the experimental system used, a bifunctional enzyme catalyzed the modification and demodification of its substrate protein, with both activities regulated by a small molecule stimulus. Here we examined how a downstream target for one or both forms of the substrate of the covalent modification cycle affected the steady-state output of the system, the sensitivity of the response to the stimulus, and the concentration of the stimulus required to provide the half-maximal response (S50). When both the modified and unmodified forms of the substrate protein were sequestered by the downstream target, the sensitivity of the response was dramatically decreased, but the S50 was only modestly affected. Conversely, when the downstream target only sequestered the unmodified form of the substrate protein, significant effects were observed on both system sensitivity and S50. Behaviors of the experimental systems were well approximated both by simple models allowing analytical solutions and by a detailed model based on the known interactions and enzymatic activities. Modeling and experimentation indicated that retroactivity may result in subsensitive responses, even if the covalent modification cycle displays significant ultrasensitivity in the absence of retroactivity. Thus, we provide examples of how a downstream target can alter the signaling properties of an upstream signal transduction covalent modification cycle.
关键词：regulatory networks ; retroactivity ; sensitivity ; signal transduction
