Multistep phosphorylation systems: tunable components of biological signaling circuits.
Bottom Line: According to our model, linear patterns of phosphorylation along disordered protein segments determine the signal-response function of a multisite phosphorylation switch.Here we discuss the general advantages and engineering principles of multisite phosphorylation networks as processors of kinase signals.We also address the idea of using the mechanistic logic of linear multisite phosphorylation networks to design circuits for synthetic biology applications.
Affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia.Show MeSH
Mentions: Intriguingly, our studies of Cdk1-dependent multisite phosphorylation revealed that phospho-adaptor–mediated docking at primed phosphorylation sites enables Cdk1 to phosphorylate residues that are not CDK consensus sites (Koivomagi et al., 2011a). In general, CDK target sites contain either optimal consensus phosphorylation motifs (S/T-P-x-K/R) or suboptimal consensus sites (S/T-P; Songyang et al., 1994; Mok et al., 2010). However, docking via optimally positioned and primed phosphorylation sites promotes the efficient phosphorylation of secondary sites that lack the required proline in position +1 (Figure 2A). This phenomenon could prove to be very important in Cdk1 signaling because it works as a filter to prevent other proline-directed kinases from erroneously triggering these Cdk1-dependent switches. In the case of both Sic1 and another Cdk1 target Far1 (unpublished results), the non-CDK site is part of the phosphodegron (output signal). Thus the multisite network allows the phosphorylation of the output degron by Cdk1 but not by other proline-directed kinases that do not have the cyclin-Cdk1-Cks1–like scaffold structure and thus cannot read the multisite phosphorylation code. Indeed, many kinases recognize the minimal consensus sequence S/T-P, which highlights the importance of this specificity filter. The output signals of Cdk1 targets must be kept very low to prevent both premature and partial signaling via Cdk1 switches in G1, as the leaking signals could induce genomic instability (Lengronne and Schwob, 2002).
Affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia.