br Transparency document br Acknowledgements This work

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Acknowledgements This work was supported by research grant G092715N of the Research Foundation Flanders (FWO). The authors are indebted to Drs. V. Baekelandt and E. Lobbestael (Research Group for Neurobiology and Gene Therapy, KU Leuven) for stimulating discussions and helpful assistance.
Introduction Death associated protein kinase 1 (DAPK1), is a calcium/calmodulin (Ca2+/CaM) regulated serine/threonine kinase located in human chromosomal locus 9q34.1 (Ren et al., 2018). It was originally identified by Deiss et al. (1995) in a genetic screen in which an antisense library was used to detect genes necessary for interferon (IFN-γ) -induced death in HeLa cells (Bialik et al., 2004; Oikonomou et al., 2016; Tu et al., 2010). DAPK1 positively mediates cell death in a wide array of cell systems (Cao et al., 2018; Cohen et al., 1999; Deiss et al., 1995; Inbal et al., 1997; Jang et al., 2002; Lin et al., 2010; Tu et al., 2010; Yamamoto et al., 2002). Several studies have shown that the activity of DAPK1 is not only restricted in cell death but it plays a major role as pro-survival mediator for the cell which reveals the conflicting activities of DAPK1 in cell physiology from one side and opens the doors for further investigations to explore the role of such enzyme (Inbal et al., 1997; Zalckvar et al., 2009). The DAPK1 gene is well conserved through evolution in different invertebrates such as C. elegans,chordates and mammals (Shoval et al., 2011; Tong et al., 2009). This Dorsomorphin microfilament-associated Ca2+/(CaM)-dependent kinase has a unique multidomain structure, including modules that mediate protein–protein interactions such as ankyrin repeats and the death domain (Cohen et al., 1997). DAPK1, is highly abundant in the brain (Wang et al., 2017) and studies have shown its association with multiple neuronal injuries related to nervous system diseases (Mor et al., 2012; Singh et al., 2016). Recently, it has been shown the implication of DAPK1 in multiple immunity system signaling such as the inflammation and innate immunity (Song et al., 2018). The expression of DAPK1 needs to be mediated as it may serve as a target for therapeutic intervention in the treatment of neurodegeneration. In the current review we aimed to shed the light on the different pathways of cell signaling that DAPK1 is involved in and take a closer look on its role in the nervous system.
DAPK1 structure and family members DAPK1 was the first described as a member of serine/threonine kinases family, this later includes at least four other kinases that share a significant homology in the catalytic domain with DAPK1 (Inbal et al., 2000; Kawai et al., 1999). ZIP(Dlk)-kinase, a serine/threonine kinase with a C-terminal leucine zipper domain, and DAPK1- related protein-1 (DRP-1) are both closely related to DAPK1, and their catalytic domains show identity with that of DAPK1 (Kögel et al., 1998). A close examination of DAPK1 structure shows a high degree of similarity to other kinases. DAPK1 kinase domain has a classical 12 subdomains composition typical of serine/ threonine kinases followed by a region that shares high homology with the calmodulin regulatory domains of other kinases. DAPK1 has two P-loop motifs structures with beta-sheets in the N-terminal and alpha-helices in the C-terminal. In the middle the catalytic domain eight ankyrin repeats were identified (Deiss et al., 1995) (Fig. 1). The ankyrin repeat is a 33AA motif of protein that mediates protein-protein interactions (Mosavi et al., 2004). The P-loop is a nucleotide ATP/GTP binding motif found in many proteins (Saraste et al., 1990). Inbal et al. (2000) and Tereshko et al. (2001) have reported that the crystal structure of the DAPK1 catalytic domain at high resolution has revealed an unusual highly basic structured loop in the N-terminal domain. The location of the loop in DAPK1 catalytic structure near the peptide recognition region raises the possibility that this could be a site of interaction with a regulatory protein or a site of modification in DAPK1 that would regulate its kinase activity. The cytoskeletal binding domain mediates the interaction between proteins and the cytoskeleton (Hoeflich et al., 2004) (Fig. 1).