Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition

Soundararajan, Meera, Roos, Annette, Savitsky, Pavel, Filippakopoulos, Panagis, Kettenbach, Arminja, Olsen, Jesper, Gerber, Scott, Eswaran, Jeyanthy, Knapp, Stefan and Elkins, Jonathan (2013) Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition. Structure, 21 (6). pp. 986-996. ISSN 0969-2126

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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.

Item Type:	Article
Subjects:	C100 Biology
Department:	Faculties > Health and Life Sciences > Applied Sciences
Depositing User:	Ellen Cole
Date Deposited:	26 Jul 2013 11:19
Last Modified:	12 Oct 2019 18:27
URI:	http://nrl.northumbria.ac.uk/id/eprint/13282

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