3k2l | pdb_00003k2l

Crystal Structure of dual-specificity tyrosine phosphorylation regulated kinase 2 (DYRK2)

Structural highlights

3k2l is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	CL, NA, SO4
NonStd Res:	PTR, SEP, TPO
Gene:	DYRK2 (HUMAN)
Activity:	Dual-specificity kinase, with EC number 2.7.12.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[DYRK2_HUMAN] Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser-641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition.,Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach AN, Olsen JV, Gerber SA, Eswaran J, Knapp S, Elkins JM Structure. 2013 Jun 4;21(6):986-96. doi: 10.1016/j.str.2013.03.012. Epub 2013 May, 9. PMID:23665168^[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, Joost HG. Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J Biol Chem. 1998 Oct 2;273(40):25893-902. PMID:9748265
↑ Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, Proud CG. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem J. 2001 May 1;355(Pt 3):609-15. PMID:11311121
↑ Wang X, Li W, Parra JL, Beugnet A, Proud CG. The C terminus of initiation factor 4E-binding protein 1 contains multiple regulatory features that influence its function and phosphorylation. Mol Cell Biol. 2003 Mar;23(5):1546-57. PMID:12588975
↑ Skurat AV, Dietrich AD. Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases. J Biol Chem. 2004 Jan 23;279(4):2490-8. Epub 2003 Oct 30. PMID:14593110 doi:10.1074/jbc.M301769200
↑ Auld GC, Campbell DG, Morrice N, Cohen P. Identification of calcium-regulated heat-stable protein of 24 kDa (CRHSP24) as a physiological substrate for PKB and RSK using KESTREL. Biochem J. 2005 Aug 1;389(Pt 3):775-83. PMID:15910284 doi:10.1042/BJ20050733
↑ Cole AR, Causeret F, Yadirgi G, Hastie CJ, McLauchlan H, McManus EJ, Hernandez F, Eickholt BJ, Nikolic M, Sutherland C. Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J Biol Chem. 2006 Jun 16;281(24):16591-8. Epub 2006 Apr 12. PMID:16611631 doi:10.1074/jbc.M513344200
↑ Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature. 2006 Jun 1;441(7093):646-50. Epub 2006 Mar 1. PMID:16511445 doi:10.1038/nature04631
↑ Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K. DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell. 2007 Mar 9;25(5):725-38. PMID:17349958 doi:10.1016/j.molcel.2007.02.007
↑ Yoshida K. Role for DYRK family kinases on regulation of apoptosis. Biochem Pharmacol. 2008 Dec 1;76(11):1389-94. doi: 10.1016/j.bcp.2008.05.021., Epub 2008 Jul 2. PMID:18599021 doi:10.1016/j.bcp.2008.05.021
↑ Varjosalo M, Bjorklund M, Cheng F, Syvanen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He WW, Ojala P, Taipale J. Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell. 2008 May 2;133(3):537-48. doi: 10.1016/j.cell.2008.02.047. PMID:18455992 doi:10.1016/j.cell.2008.02.047
↑ Maddika S, Chen J. Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase. Nat Cell Biol. 2009 Apr;11(4):409-19. doi: 10.1038/ncb1848. Epub 2009 Mar 15. PMID:19287380 doi:10.1038/ncb1848
↑ Taira N, Mimoto R, Kurata M, Yamaguchi T, Kitagawa M, Miki Y, Yoshida K. DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells. J Clin Invest. 2012 Mar 1;122(3):859-72. doi: 10.1172/JCI60818. Epub 2012 Feb 6. PMID:22307329 doi:10.1172/JCI60818
↑ Perez M, Garcia-Limones C, Zapico I, Marina A, Schmitz ML, Munoz E, Calzado MA. Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways. J Mol Cell Biol. 2012 Oct;4(5):316-30. doi: 10.1093/jmcb/mjs047. Epub 2012 Aug 9. PMID:22878263 doi:10.1093/jmcb/mjs047
↑ Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach AN, Olsen JV, Gerber SA, Eswaran J, Knapp S, Elkins JM. Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition. Structure. 2013 Jun 4;21(6):986-96. doi: 10.1016/j.str.2013.03.012. Epub 2013 May, 9. PMID:23665168 doi:10.1016/j.str.2013.03.012

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OCA

[1] Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, Joost HG. Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J Biol Chem. 1998 Oct 2;273(40):25893-902. PMID:9748265

[2] Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, Proud CG. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem J. 2001 May 1;355(Pt 3):609-15. PMID:11311121

[3] Wang X, Li W, Parra JL, Beugnet A, Proud CG. The C terminus of initiation factor 4E-binding protein 1 contains multiple regulatory features that influence its function and phosphorylation. Mol Cell Biol. 2003 Mar;23(5):1546-57. PMID:12588975

[4] Skurat AV, Dietrich AD. Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases. J Biol Chem. 2004 Jan 23;279(4):2490-8. Epub 2003 Oct 30. PMID:14593110 doi:10.1074/jbc.M301769200

[5] Auld GC, Campbell DG, Morrice N, Cohen P. Identification of calcium-regulated heat-stable protein of 24 kDa (CRHSP24) as a physiological substrate for PKB and RSK using KESTREL. Biochem J. 2005 Aug 1;389(Pt 3):775-83. PMID:15910284 doi:10.1042/BJ20050733

[6] Cole AR, Causeret F, Yadirgi G, Hastie CJ, McLauchlan H, McManus EJ, Hernandez F, Eickholt BJ, Nikolic M, Sutherland C. Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J Biol Chem. 2006 Jun 16;281(24):16591-8. Epub 2006 Apr 12. PMID:16611631 doi:10.1074/jbc.M513344200

[7] Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature. 2006 Jun 1;441(7093):646-50. Epub 2006 Mar 1. PMID:16511445 doi:10.1038/nature04631

[8] Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K. DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell. 2007 Mar 9;25(5):725-38. PMID:17349958 doi:10.1016/j.molcel.2007.02.007

[9] Yoshida K. Role for DYRK family kinases on regulation of apoptosis. Biochem Pharmacol. 2008 Dec 1;76(11):1389-94. doi: 10.1016/j.bcp.2008.05.021., Epub 2008 Jul 2. PMID:18599021 doi:10.1016/j.bcp.2008.05.021

[10] Varjosalo M, Bjorklund M, Cheng F, Syvanen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He WW, Ojala P, Taipale J. Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell. 2008 May 2;133(3):537-48. doi: 10.1016/j.cell.2008.02.047. PMID:18455992 doi:10.1016/j.cell.2008.02.047

[11] Maddika S, Chen J. Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase. Nat Cell Biol. 2009 Apr;11(4):409-19. doi: 10.1038/ncb1848. Epub 2009 Mar 15. PMID:19287380 doi:10.1038/ncb1848

[12] Taira N, Mimoto R, Kurata M, Yamaguchi T, Kitagawa M, Miki Y, Yoshida K. DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells. J Clin Invest. 2012 Mar 1;122(3):859-72. doi: 10.1172/JCI60818. Epub 2012 Feb 6. PMID:22307329 doi:10.1172/JCI60818

[13] Perez M, Garcia-Limones C, Zapico I, Marina A, Schmitz ML, Munoz E, Calzado MA. Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways. J Mol Cell Biol. 2012 Oct;4(5):316-30. doi: 10.1093/jmcb/mjs047. Epub 2012 Aug 9. PMID:22878263 doi:10.1093/jmcb/mjs047

[14] Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach AN, Olsen JV, Gerber SA, Eswaran J, Knapp S, Elkins JM. Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition. Structure. 2013 Jun 4;21(6):986-96. doi: 10.1016/j.str.2013.03.012. Epub 2013 May, 9. PMID:23665168 doi:10.1016/j.str.2013.03.012

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3k2l | pdb_00003k2l

Crystal Structure of dual-specificity tyrosine phosphorylation regulated kinase 2 (DYRK2)

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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