TY - JOUR
T1 - Structures of down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition
AU - Soundararajan, M.
AU - Roos, A.K.
AU - Savitsky, P.
AU - Filippakopoulos, P.
AU - Kettenbach, A.N.
AU - Olsen, J.V.
AU - Gerber, Sophie
AU - Eswaran, J.
AU - Knapp, S.
AU - Elkins, J.M.
PY - 2013/6/4
Y1 - 2013/6/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878851513&partnerID=8YFLogxK
U2 - 10.1016/j.str.2013.03.012
DO - 10.1016/j.str.2013.03.012
M3 - Journal article
C2 - 23665168
AN - SCOPUS:84878851513
SN - 0969-2126
VL - 21
SP - 986
EP - 996
JO - Structure
JF - Structure
IS - 6
ER -
