| Structural highlights
Function
DAPK1_HUMAN Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript-selective translation inhibition.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] Isoform 2 cannot induce apoptosis but can induce membrane blebbing.[16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30]
Publication Abstract from PubMed
Death-associated protein kinase 1 (DAPK1) is a 160 kDa serine/threonine protein kinase that belongs to the Ca(2+)/calmodulin-dependent protein kinase subfamily. DAPK1 is a possible target for the treatment of acute ischemic stroke and endometrial adenocarcinomas. In the present study, we investigated the binding characteristics of 17 natural flavonoids to DAPK1 using a 1-anilinonaphthalene-8-sulfonic acid competitive binding assay and revealed that morin was the strongest binder among the selected compounds. The crystallographic analysis of DAPK1 and 7 selected flavonoid complexes revealed the structure-binding affinity relationship in atomic-level detail. It was suggested that the high affinity of morin could be accounted for by the ionic interaction between 2'-OH and K42 and that such an interaction would not take place with either cyclin-dependent protein kinases or PIM kinases because of their broader entrance regions. Thus, morin would be a more selective inhibitor of DAPK1 than either of these other types of kinases. In addition, we found that the binding of kaempferol to DAPK1 was associated with a chloride ion. The present study provides a better understanding of the molecular properties of the ATP site of DAPK1 and may be useful for the design of specific DAPK1 inhibitors.
Structural Insight into the Interactions between Death-Associated Protein Kinase 1 and Natural Flavonoids.,Yokoyama T, Kosaka Y, Mizuguchi M J Med Chem. 2015 Sep 24;58(18):7400-8. doi: 10.1021/acs.jmedchem.5b00893. Epub, 2015 Sep 4. PMID:26322379[31]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A. Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 1995 Jan 1;9(1):15-30. PMID:7828849
- ↑ Inbal B, Shani G, Cohen O, Kissil JL, Kimchi A. Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis. Mol Cell Biol. 2000 Feb;20(3):1044-54. PMID:10629061
- ↑ Shohat G, Spivak-Kroizman T, Cohen O, Bialik S, Shani G, Berrisi H, Eisenstein M, Kimchi A. The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism. J Biol Chem. 2001 Dec 14;276(50):47460-7. Epub 2001 Sep 28. PMID:11579085 doi:10.1074/jbc.M105133200
- ↑ Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A. DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol. 2002 Apr 29;157(3):455-68. Epub 2002 Apr 29. PMID:11980920 doi:10.1083/jcb.200109094
- ↑ Tian JH, Das S, Sheng ZH. Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated protein (DAP) kinase regulates its interaction with Munc18. J Biol Chem. 2003 Jul 11;278(28):26265-74. Epub 2003 May 2. PMID:12730201 doi:10.1074/jbc.M300492200
- ↑ Shani G, Marash L, Gozuacik D, Bialik S, Teitelbaum L, Shohat G, Kimchi A. Death-associated protein kinase phosphorylates ZIP kinase, forming a unique kinase hierarchy to activate its cell death functions. Mol Cell Biol. 2004 Oct;24(19):8611-26. PMID:15367680 doi:10.1128/MCB.24.19.8611-8626.2004
- ↑ Eisenberg-Lerner A, Kimchi A. DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress. Cell Death Differ. 2007 Nov;14(11):1908-15. Epub 2007 Aug 17. PMID:17703233 doi:10.1038/sj.cdd.4402212
- ↑ Houle F, Poirier A, Dumaresq J, Huot J. DAP kinase mediates the phosphorylation of tropomyosin-1 downstream of the ERK pathway, which regulates the formation of stress fibers in response to oxidative stress. J Cell Sci. 2007 Oct 15;120(Pt 20):3666-77. Epub 2007 Sep 25. PMID:17895359 doi:10.1242/jcs.003251
- ↑ Lin Y, Stevens C, Hrstka R, Harrison B, Fourtouna A, Pathuri S, Vojtesek B, Hupp T. An alternative transcript from the death-associated protein kinase 1 locus encoding a small protein selectively mediates membrane blebbing. FEBS J. 2008 May;275(10):2574-84. doi: 10.1111/j.1742-4658.2008.06404.x. Epub, 2008 Apr 15. PMID:18422656 doi:10.1111/j.1742-4658.2008.06404.x
- ↑ Harrison B, Kraus M, Burch L, Stevens C, Craig A, Gordon-Weeks P, Hupp TR. DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing. J Biol Chem. 2008 Apr 11;283(15):9999-10014. doi: 10.1074/jbc.M706040200. Epub, 2008 Jan 14. PMID:18195017 doi:10.1074/jbc.M706040200
- ↑ Mukhopadhyay R, Ray PS, Arif A, Brady AK, Kinter M, Fox PL. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Mol Cell. 2008 Nov 7;32(3):371-82. doi: 10.1016/j.molcel.2008.09.019. PMID:18995835 doi:10.1016/j.molcel.2008.09.019
- ↑ Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M, Sabanay H, Pinkas-Kramarski R, Kimchi A. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep. 2009 Mar;10(3):285-92. doi: 10.1038/embor.2008.246. Epub 2009 Jan 30. PMID:19180116 doi:10.1038/embor.2008.246
- ↑ Stevens C, Lin Y, Harrison B, Burch L, Ridgway RA, Sansom O, Hupp T. Peptide combinatorial libraries identify TSC2 as a death-associated protein kinase (DAPK) death domain-binding protein and reveal a stimulatory role for DAPK in mTORC1 signaling. J Biol Chem. 2009 Jan 2;284(1):334-44. doi: 10.1074/jbc.M805165200. Epub 2008 Oct, 30. PMID:18974095 doi:10.1074/jbc.M805165200
- ↑ Lee TH, Chen CH, Suizu F, Huang P, Schiene-Fischer C, Daum S, Zhang YJ, Goate A, Chen RH, Zhou XZ, Lu KP. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell. 2011 Apr 22;42(2):147-59. doi: 10.1016/j.molcel.2011.03.005. Epub 2011 , Apr 14. PMID:21497122 doi:10.1016/j.molcel.2011.03.005
- ↑ Shoval Y, Berissi H, Kimchi A, Pietrokovski S. New modularity of DAP-kinases: alternative splicing of the DRP-1 gene produces a ZIPk-like isoform. PLoS One. 2011 Mar 8;6(2):e17344. doi: 10.1371/journal.pone.0017344. PMID:21408167 doi:10.1371/journal.pone.0017344
- ↑ Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A. Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 1995 Jan 1;9(1):15-30. PMID:7828849
- ↑ Inbal B, Shani G, Cohen O, Kissil JL, Kimchi A. Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis. Mol Cell Biol. 2000 Feb;20(3):1044-54. PMID:10629061
- ↑ Shohat G, Spivak-Kroizman T, Cohen O, Bialik S, Shani G, Berrisi H, Eisenstein M, Kimchi A. The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism. J Biol Chem. 2001 Dec 14;276(50):47460-7. Epub 2001 Sep 28. PMID:11579085 doi:10.1074/jbc.M105133200
- ↑ Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A. DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol. 2002 Apr 29;157(3):455-68. Epub 2002 Apr 29. PMID:11980920 doi:10.1083/jcb.200109094
- ↑ Tian JH, Das S, Sheng ZH. Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated protein (DAP) kinase regulates its interaction with Munc18. J Biol Chem. 2003 Jul 11;278(28):26265-74. Epub 2003 May 2. PMID:12730201 doi:10.1074/jbc.M300492200
- ↑ Shani G, Marash L, Gozuacik D, Bialik S, Teitelbaum L, Shohat G, Kimchi A. Death-associated protein kinase phosphorylates ZIP kinase, forming a unique kinase hierarchy to activate its cell death functions. Mol Cell Biol. 2004 Oct;24(19):8611-26. PMID:15367680 doi:10.1128/MCB.24.19.8611-8626.2004
- ↑ Eisenberg-Lerner A, Kimchi A. DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress. Cell Death Differ. 2007 Nov;14(11):1908-15. Epub 2007 Aug 17. PMID:17703233 doi:10.1038/sj.cdd.4402212
- ↑ Houle F, Poirier A, Dumaresq J, Huot J. DAP kinase mediates the phosphorylation of tropomyosin-1 downstream of the ERK pathway, which regulates the formation of stress fibers in response to oxidative stress. J Cell Sci. 2007 Oct 15;120(Pt 20):3666-77. Epub 2007 Sep 25. PMID:17895359 doi:10.1242/jcs.003251
- ↑ Lin Y, Stevens C, Hrstka R, Harrison B, Fourtouna A, Pathuri S, Vojtesek B, Hupp T. An alternative transcript from the death-associated protein kinase 1 locus encoding a small protein selectively mediates membrane blebbing. FEBS J. 2008 May;275(10):2574-84. doi: 10.1111/j.1742-4658.2008.06404.x. Epub, 2008 Apr 15. PMID:18422656 doi:10.1111/j.1742-4658.2008.06404.x
- ↑ Harrison B, Kraus M, Burch L, Stevens C, Craig A, Gordon-Weeks P, Hupp TR. DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing. J Biol Chem. 2008 Apr 11;283(15):9999-10014. doi: 10.1074/jbc.M706040200. Epub, 2008 Jan 14. PMID:18195017 doi:10.1074/jbc.M706040200
- ↑ Mukhopadhyay R, Ray PS, Arif A, Brady AK, Kinter M, Fox PL. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Mol Cell. 2008 Nov 7;32(3):371-82. doi: 10.1016/j.molcel.2008.09.019. PMID:18995835 doi:10.1016/j.molcel.2008.09.019
- ↑ Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M, Sabanay H, Pinkas-Kramarski R, Kimchi A. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep. 2009 Mar;10(3):285-92. doi: 10.1038/embor.2008.246. Epub 2009 Jan 30. PMID:19180116 doi:10.1038/embor.2008.246
- ↑ Stevens C, Lin Y, Harrison B, Burch L, Ridgway RA, Sansom O, Hupp T. Peptide combinatorial libraries identify TSC2 as a death-associated protein kinase (DAPK) death domain-binding protein and reveal a stimulatory role for DAPK in mTORC1 signaling. J Biol Chem. 2009 Jan 2;284(1):334-44. doi: 10.1074/jbc.M805165200. Epub 2008 Oct, 30. PMID:18974095 doi:10.1074/jbc.M805165200
- ↑ Lee TH, Chen CH, Suizu F, Huang P, Schiene-Fischer C, Daum S, Zhang YJ, Goate A, Chen RH, Zhou XZ, Lu KP. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell. 2011 Apr 22;42(2):147-59. doi: 10.1016/j.molcel.2011.03.005. Epub 2011 , Apr 14. PMID:21497122 doi:10.1016/j.molcel.2011.03.005
- ↑ Shoval Y, Berissi H, Kimchi A, Pietrokovski S. New modularity of DAP-kinases: alternative splicing of the DRP-1 gene produces a ZIPk-like isoform. PLoS One. 2011 Mar 8;6(2):e17344. doi: 10.1371/journal.pone.0017344. PMID:21408167 doi:10.1371/journal.pone.0017344
- ↑ Yokoyama T, Kosaka Y, Mizuguchi M. Structural Insight into the Interactions between Death-Associated Protein Kinase 1 and Natural Flavonoids. J Med Chem. 2015 Sep 24;58(18):7400-8. doi: 10.1021/acs.jmedchem.5b00893. Epub, 2015 Sep 4. PMID:26322379 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00893
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