title: Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.
abstract: Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs) play key roles in brain development, regulation of splicing, and apoptosis, and are potential drug targets for neurodegenerative diseases and cancer. We present crystal structures of one representative member of each DYRK subfamily: DYRK1A with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA and DH (DYRK homology) box regions. The current activation model suggests that DYRKs are Ser/Thr kinases that only autophosphorylate the second tyrosine of the activation loop YxY motif during protein translation. The structures explain the roles of this tyrosine and of the DH box in DYRK activation and provide a structural model for DYRK substrate recognition. Phosphorylation of a library of naturally occurring peptides identified substrate motifs that lack proline in the P+1 position, suggesting that DYRK1A is not a strictly proline-directed kinase. Our data also show that DYRK1A wild-type and Y321F mutant retain tyrosine autophosphorylation activity.
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Meera
authors.initials: M
authors.lastname: Soundararajan
authors.forename: Annette K
authors.initials: AK
authors.lastname: Roos
authors.forename: Pavel
authors.initials: P
authors.lastname: Savitsky
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Arminja N
authors.initials: AN
authors.lastname: Kettenbach
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
authors.forename: Scott A
authors.initials: SA
authors.lastname: Gerber
authors.forename: Jeyanthy
authors.initials: J
authors.lastname: Eswaran
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Elkins
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D004314:Down Syndrome / Q000201:enzymology*; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013379:Substrate Specificity; D013912:Threonine / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012694:Serine; D013912:Threonine; D000097603:Dyrk Kinases