The Library
Ultrasensitivity in posphorylation-dephosphorylation cycles with little substrate
Tools
Mac Gabhann, Feilim, Martins, Bruno M. C. and Swain, Peter S. (2013) Ultrasensitivity in posphorylation-dephosphorylation cycles with little substrate. PLoS Computational Biology, 9 (8). e1003175. doi:10.1371/journal.pcbi.1003175 ISSN 1553-7358.
Research output not available from this repository.
Request-a-Copy directly from author or use local Library Get it For Me service.
Official URL: http://dx.doi.org/10.1371/journal.pcbi.1003175
Abstract
Cellular decision-making is driven by dynamic behaviours, such as the preparations for sunrise enabled by circadian rhythms and the choice of cell fates enabled by positive feedback. Such behaviours are often built upon ultrasensitive responses where a linear change in input generates a sigmoidal change in output. Phosphorylation-dephosphorylation cycles are one means to generate ultrasensitivity. Using bioinformatics, we show that in vivo levels of kinases and phosphatases frequently exceed the levels of their corresponding substrates in budding yeast. This result is in contrast to the conditions often required by zero-order ultrasensitivity, perhaps the most well known means for how such cycles become ultrasensitive. We therefore introduce a mechanism to generate ultrasensitivity when numbers of enzymes are higher than numbers of substrates. Our model combines distributive and non-distributive actions of the enzymes with two-stage binding and concerted allosteric transitions of the substrate. We use analytical and numerical methods to calculate the Hill number of the response. For a substrate with phosphosites, we find an upper bound of the Hill number of , and so even systems with a single phosphosite can be ultrasensitive. Two-stage binding, where an enzyme must first bind to a binding site on the substrate before it can access the substrate's phosphosites, allows the enzymes to sequester the substrate. Such sequestration combined with competition for each phosphosite provides an intuitive explanation for the sigmoidal shifts in levels of phosphorylated substrate. Additionally, we find cases for which the response is not monotonic, but shows instead a peak at intermediate levels of input. Given its generality, we expect the mechanism described by our model to often underlay decision-making circuits in eukaryotic cells.
Item Type: | Journal Article | ||||
---|---|---|---|---|---|
Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | PLoS Computational Biology | ||||
Publisher: | Public Library of Science | ||||
ISSN: | 1553-7358 | ||||
Official Date: | 8 August 2013 | ||||
Dates: |
|
||||
Volume: | 9 | ||||
Number: | 8 | ||||
Article Number: | e1003175 | ||||
DOI: | 10.1371/journal.pcbi.1003175 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Open Access (Creative Commons) |
Request changes or add full text files to a record
Repository staff actions (login required)
View Item |