title: Efficient modification of alpha-synuclein serine 129 by protein kinase CK1 requires phosphorylation of tyrosine 125 as a priming event.
abstract: S129-phosphorylated alpha-synuclein (α-syn) is abundantly found in Lewy-body inclusions of Parkinson's disease patients. Residues neighboring S129 include the α-syn tyrosine phosphorylation sites Y125, Y133, and Y136. Here, we use time-resolved NMR spectroscopy to delineate atomic resolution insights into the modification behaviors of different serine and tyrosine kinases targeting these sites and show that Y125 phosphorylation constitutes a necessary priming event for the efficient modification of S129 by CK1, both in reconstituted kinase reactions and mammalian cell lysates. These results suggest that α-syn Y125 phosphorylation augments S129 modification under physiological in vivo conditions.
authors.affiliation: In-Cell NMR Laboratory, Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin) , Robert-Rössle Strasse 10, 13125 Berlin, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Kosten
authors.forename: Andres
authors.initials: A
authors.lastname: Binolfi
authors.forename: Marchel
authors.initials: M
authors.lastname: Stuiver
authors.forename: Silvia
authors.initials: S
authors.lastname: Verzini
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Theillet
authors.forename: Beata
authors.initials: B
authors.lastname: Bekei
authors.forename: Marleen
authors.initials: M
authors.lastname: van Rossum
authors.forename: Philipp
authors.initials: P
authors.lastname: Selenko
mesh_terms: D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010766:Phosphorylation / Q000502:physiology; D012694:Serine / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D012694:Serine; D047389:Casein Kinase I
keywords: Alpha-synuclein; NMR; Parkinson’s disease; casein kinase 1; kinetics; phosphorylation