title: Kinetic modulation of a disordered protein domain by phosphorylation.
abstract: Phosphorylation is a major post-translational mechanism of regulation that frequently targets disordered protein domains, but it remains unclear how phosphorylation modulates disordered states of proteins. Here we determine the kinetics and energetics of a disordered protein domain the kinase-inducible domain (KID) of the transcription factor CREB and that of its phosphorylated form pKID, using high-throughput molecular dynamic simulations. We identify the presence of a metastable, partially ordered state with a 60-fold slowdown in conformational kinetics that arises due to phosphorylation, kinetically stabilizing residues known to participate in an early binding intermediate. We show that this effect is only partially reconstituted by mutation to glutamate, indicating that the phosphate is uniquely required for the long-lived state to arise. This mechanism of kinetic modulation could be important for regulation beyond conformational equilibrium shifts.
authors.affiliation: Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Stanley
authors.affiliation: Joint BSC-IRB-CRG Research Programme in Computational Biology, Barcelona Supercomputing Center - BSC, Jordi Girona, 29, 08034 Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Esteban-Martín
authors.affiliation: 1] Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003 Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats, Passeig Lluis Companys 23, 08010 Barcelona, Spain.
authors.forename: Gianni
authors.initials: G
authors.lastname: De Fabritiis
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D000596:Amino Acids; D017362:Cyclic AMP Response Element-Binding Protein