title: Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity.
abstract: Regulation of biological processes often involves phosphorylation of intrinsically disordered protein regions, thereby modulating protein interactions. Initiation of DNA replication in yeast requires elimination of the cyclin-dependent kinase inhibitor Sic1 via the SCF(Cdc4) ubiquitin ligase. Intriguingly, the substrate adapter subunit Cdc4 binds to Sic1 only after phosphorylation of a minimum of any six of the nine cyclin-dependent kinase sites on Sic1. To investigate the physical basis of this ultrasensitive interaction, we consider a mean-field statistical mechanical model for the electrostatic interactions between a single receptor site and a conformationally disordered polyvalent ligand. The formulation treats phosphorylation sites as negative contributions to the total charge of the ligand and addresses its interplay with the strength of the favorable ligand-receptor contact. Our model predicts a threshold number of phosphorylation sites for receptor-ligand binding, suggesting that ultrasensitivity in the Sic1-Cdc4 system may be driven at least in part by cumulative electrostatic interactions. This hypothesis is supported by experimental affinities of Cdc4 for Sic1 fragments with different total charges. Thus, polyelectrostatic interactions may provide a simple yet powerful framework for understanding the modulation of protein interactions by multiple phosphorylation sites in disordered protein regions.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Mikael
authors.initials: M
authors.lastname: Borg
authors.forename: Tanja
authors.initials: T
authors.lastname: Mittag
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Mike
authors.initials: M
authors.lastname: Tyers
authors.forename: Julie D
authors.initials: JD
authors.lastname: Forman-Kay
authors.forename: Hue Sun
authors.initials: HS
authors.lastname: Chan
mesh_terms: D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D004261:DNA Replication / Q000502:physiology*; D044783:F-Box Proteins; D008024:Ligands; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D015003:Yeasts
chemical_list: C080443:CDC4 protein, S cerevisiae; D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D044783:F-Box Proteins; D008024:Ligands; C086926:SIC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D044767:Ubiquitin-Protein Ligases