DAPK3: Human Death Associated Kinase 3
PDB Code: 2J90
The death-associated protein (DAP) kinase family includes three protein kinases, DAP kinase, DAP kinase-related protein 1, and DAPK3 (ZIPK), also called dual leucine zipper kinase . Members of this family mediate cell death initiated by various external and internal signals, including tumor necrosis factor alpha (TNF-α), Fas, transforming growth factor β and detachment from the extracellular matrix. One common feature of DAPK induced death is membrane blebbing, which has been attributed to increased phosphorylation of the regulatory light chain of myosin II (MLC). Sequence alignment of the catalytic domains showed that DAPKs share a unique stretch of basic amino acids at the N-terminus unique to these kinases referred to as the "fingerprint" of the DAPK family.
DAPK3 kinase localizes to both the nucleus and the cytoplasm and fractionates as monomeric and trimeric forms. Significantly, modification of the DAP kinase phosphorylation sites influences both the localization and oligomerization status of ZIP kinase. DAPKs are Ca2+/calmodulin (CaM)-regulated kinases associated with actin microfilaments. However, DAPK3 lacks the CaM regulatory domain, suggesting different modes of activation. In addition to the N-terminal catalytic domain, DAPK3 contains a leucine zipper structure at its C terminus which is believed to mediate homodimerization.
DAPK3 may be present in the cytoplasm as well as in the nucleus. Similar to other DAPKs, cytoplasmic DAPK3 has death-inducing properties, including phosphorylation of MLC and induction of membrane blebbing. L ocalization of DAPK3 is regulated during the cell cycle and DAPK3 has been reported to be associated with centrosomes, centromeres and contractile ring during prophase and early metaphase. In the nucleus DAPK3 has been shown to bind to the ATF4 transcription factor and it phosphorylates centromere-specific histones during mitosis.
Interestingly DAPK3 has also been identified as a regulator of Ca2+ sensitization in smooth muscle cells by controlling the phosphorylation of myosin phosphatase (SMPP-1M) and the inhibitor protein CPI17. Phosphorylation of SMPP-1M and CPI17 by DAPK3 inhibits phosphatase activity towards myosin and causes profound Ca2+ sensitization and contraction in smooth muscle. DAPK3 also directly phosphorylates both muscle and non-muscle myosin. The highly selective actions of DAPK3 in the control of myosin phosphorylation makes this enzyme an interesting candidate for the development of novel therapeutics to treat smooth muscle related disorders such as hypertension or asthma.
We determined the structure (2J90) of DAPK3 in complex with the inhibitor Pyridone 6 (2-(1,1-Dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinolin-7-one). A potent cell-permeable, and ATP-competitive inhibitor that has been described to inhibit Janus protein tyrosine kinases (JAKs) and the related receptor tyrosine kinase Tyk2.
In addition, we determined the structure of unphosphorylated DAPK3 in complex with a beta-carboline (3BHY) and an imidazo pyridazine (3BQR) inhibitor, respectively.
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