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

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Structures of down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. / Soundararajan, M.; Roos, A.K.; Savitsky, P.; Filippakopoulos, P.; Kettenbach, A.N.; Olsen, J.V.; Gerber, Sophie; Eswaran, J.; Knapp, S.; Elkins, J.M.

In: Structure, Vol. 21, No. 6, 04.06.2013, p. 986-996.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Soundararajan, M, Roos, AK, Savitsky, P, Filippakopoulos, P, Kettenbach, AN, Olsen, JV, Gerber, S, Eswaran, J, Knapp, S & Elkins, JM 2013, 'Structures of down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition', Structure, vol. 21, no. 6, pp. 986-996. https://doi.org/10.1016/j.str.2013.03.012

APA

Soundararajan, M., Roos, A. K., Savitsky, P., Filippakopoulos, P., Kettenbach, A. N., Olsen, J. V., Gerber, S., Eswaran, J., Knapp, S., & Elkins, J. M. (2013). Structures of down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. Structure, 21(6), 986-996. https://doi.org/10.1016/j.str.2013.03.012

Vancouver

Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach AN, Olsen JV et al. Structures of down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. Structure. 2013 Jun 4;21(6):986-996. https://doi.org/10.1016/j.str.2013.03.012

Author

Soundararajan, M. ; Roos, A.K. ; Savitsky, P. ; Filippakopoulos, P. ; Kettenbach, A.N. ; Olsen, J.V. ; Gerber, Sophie ; Eswaran, J. ; Knapp, S. ; Elkins, J.M. / Structures of down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. In: Structure. 2013 ; Vol. 21, No. 6. pp. 986-996.

Bibtex

@article{9223370352024bbba2b9ec5036b9440b,
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.",
author = "M. Soundararajan and A.K. Roos and P. Savitsky and P. Filippakopoulos and A.N. Kettenbach and J.V. Olsen and Sophie Gerber and J. Eswaran and S. Knapp and J.M. Elkins",
year = "2013",
month = jun,
day = "4",
doi = "10.1016/j.str.2013.03.012",
language = "English",
volume = "21",
pages = "986--996",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "6",

}

RIS

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

VL - 21

SP - 986

EP - 996

JO - Structure

JF - Structure

SN - 0969-2126

IS - 6

ER -

ID: 46438843