Figure 3. Response to multisite phosphorylation in IDRs.

Multisite phosphorylation of disordered proteins can give rise to a range of signaling responses. (a) For phosphorylation at a single site, the response takes the form of a simple hyperbolic saturation curve, as would be the case for single-site phosphorylation of CREB at Ser133 and its interaction with the KIX domain of CBP^79,80. (b) In the Sic1-SCF ubiquitin ligase system⁸¹, the response to phosphorylation at multiple sites takes the form of sigmoidal threshold response curves, with cooperativity increasing as an increasing number of sites (1–6) are phosphorylated. (c) The interaction of Eco1 with the Cdc4 subunit of the SCF ubiquitin ligase⁸⁵ shows coincidence detection, where a certain threshold level of phosphorylation must be achieved before response is initiated. (d) Under conditions of genotoxic stress the affinity of the p53 transactivation domain for CBP/p300²³ increases with each successive phosphorylation event, relative to the affinities of other transcription factors (denoted TF1 and TF2). This is an example of a rheostat response. Figure adapted from ^81,85,23 with permission.