title: Multistep phosphorylation systems: tunable components of biological signaling circuits.
abstract: Multisite phosphorylation of proteins is a powerful signal processing mechanism that plays crucial roles in cell division and differentiation as well as in disease. We recently demonstrated a novel phenomenon in cell cycle regulation by showing that cyclin-dependent kinase-dependent multisite phosphorylation of a crucial substrate is performed sequentially in the N-to-C terminal direction along the disordered protein. The process is controlled by key parameters, including the distance between phosphorylation sites, the distribution of serines and threonines in sites, and the position of docking motifs. 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.
authors.affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
authors.forename: Evin
authors.initials: E
authors.lastname: Valk
authors.affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
authors.forename: Rainis
authors.initials: R
authors.lastname: Venta
authors.affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
authors.forename: Mihkel
authors.initials: M
authors.lastname: Ord
authors.affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
authors.forename: Ilona
authors.initials: I
authors.lastname: Faustova
authors.affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
authors.forename: Mardo
authors.initials: M
authors.lastname: Kõivomägi
authors.affiliation: Institute of Technology, University of Tartu, 50411 Tartu, Estonia mart.loog@ut.ee.
authors.forename: Mart
authors.initials: M
authors.lastname: Loog
mesh_terms: D000595:Amino Acid Sequence; D002454:Cell Differentiation; D002455:Cell Division; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D010750:Phosphoproteins; D029701:Saccharomyces cerevisiae Proteins; D018844:Cyclin-Dependent Kinases