Structure, activity, regulation, and inhibitor discovery for a protein kinase associated with apoptosis and neuronal death.

Death-associated protein kinase (DAPK) is a calmodulin-regulated serine/threonine protein kinase associated with neuronal cell death in animal models of disease. The recent determination of the 1.5A crystal structure of the catalytic kinase domain of DAPK, the discovery of amino acid sequence motifs with sites that are preferentially phosphorylated by this kinase, and the development of a quantitative enzyme activity assay provide a firm foundation for future studies into its regulation, the identification of its physiological substrates, and discovery of inhibitors. We summarize the relevant background and ongoing investigations that will increase our understanding of the role and regulation of this prototype death-associated kinase.