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
Related in: MedlinePlus
Mentions: Cdk1-dependent phosphorylation events often lead to the generation of phosphorylated sequence motifs (phosphodegrons) that are recognized by the ubiquitination machinery and thereby marked for destruction (Hao et al., 2007; Koivomagi et al., 2011a; Landry et al., 2012). For example, phosphorylation-dependent destruction of a Cdk1 inhibitor protein called Sic1 helps to trigger S phase in budding yeast. Cdk1, when bound to G1- and S-phase cyclins, phosphorylates Sic1 in an ordered sequence at multiple sites, leading to the formation of phosphodegrons that are recognized by the ubiquitin ligase SCF-Cdc4. The sequential phosphorylation of Sic1 and other substrates depends on three important interactions between Cdk1 complexes and the disordered substrate chain (Figure 1, A and B): the active site of Cdk1 interacts with the consensus phosphorylation site, typically S/T-P or S/T-PxK/R (Khoury et al., 2011); specific sites on the cyclin interact with docking motifs on the substrate (Holt et al., 2009); and the small adaptor protein Cks1 interacts with specific phosphorylated threonines on the substrate (Tyanova et al., 2013).
Affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia.