Several mechanisms can, in principle, give rise to ultrasensitivity, including zero-order effects, multisite phosphorylation, and competition mechanisms.
Schalm, S. S., Fingar, D. C., Sabatini, D. M. & Blenis, J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function.
This theoretical study, however, shows that a system composed of one substrate with multisite phosphorylation and a pair of kinase and phosphatase can generate autonomous spatial information, including complex stripe patterns.
Table 1 illustrates some of these examples we were able to compile readily by conducting a literature search on multisite phosphorylation and protein degradation.
In order to better understand how Cdc24 may be regulated by multisite phosphorylation and, in particular, how this phosphorylation contributes to the Bem1-dependent and actin-independent cell polarization, we set out to purify Cdc24 from yeast cells in order to identify the in vivo phosphorylation sites by mass spectrometry analysis.
Using a statistical physics approach, we study the stochastic switching behavior of a model circuit of multisite phosphorylation and dephosphorylation with feedback.
Currently, ∼40% of phosphoproteins in PRO with site information are phosphorylated on more than one site, suggesting that multisite phosphorylation is common and needs to be taken into account to develop a realistic picture of biological phosphorylation events.
Central elements of these switches are multisite phosphorylation, enzymic saturation, and amplification by cascades.
Alternatively, MRM-based approaches have been used to identify the presence of phosphorylation on key cell cycle regulatory proteins [ 22], to quantify multisite phosphorylation [ 23], and to perform quantitative proteomic analysis of cellular signaling networks [ 24].
