Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.

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 subfam...

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Main Authors: Soundararajan, M, Roos, A, Savitsky, P, Filippakopoulos, P, Kettenbach, A, Olsen, J, Gerber, SA, Eswaran, J, Knapp, S, Elkins, J
Format: Journal article
Jezik:English
Izdano: 2013
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author Soundararajan, M
Roos, A
Savitsky, P
Filippakopoulos, P
Kettenbach, A
Olsen, J
Gerber, SA
Eswaran, J
Knapp, S
Elkins, J
author_facet Soundararajan, M
Roos, A
Savitsky, P
Filippakopoulos, P
Kettenbach, A
Olsen, J
Gerber, SA
Eswaran, J
Knapp, S
Elkins, J
author_sort Soundararajan, M
collection OXFORD
description 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.
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spelling oxford-uuid:a0b14ad4-73d5-4078-b6b8-7fcc3ee6bba42022-03-27T02:07:19ZStructures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a0b14ad4-73d5-4078-b6b8-7fcc3ee6bba4EnglishSymplectic Elements at Oxford2013Soundararajan, MRoos, ASavitsky, PFilippakopoulos, PKettenbach, AOlsen, JGerber, SAEswaran, JKnapp, SElkins, JDual-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.
spellingShingle Soundararajan, M
Roos, A
Savitsky, P
Filippakopoulos, P
Kettenbach, A
Olsen, J
Gerber, SA
Eswaran, J
Knapp, S
Elkins, J
Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.
title Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.
title_full Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.
title_fullStr Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.
title_full_unstemmed Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.
title_short Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition.
title_sort structures of down syndrome kinases dyrks reveal mechanisms of kinase activation and substrate recognition
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