SLK + K00606a
SLK + K00606a: Human SLK (Ste20-like kinase) in complex with K00606a
PDB Code: 2UV2
The STE20 kinase SLK is a ser/thr kinase and a member of group II of germinal center kinases (GCKs), which includes MST1-3, SOK1 and LOK. SLK has been reported to be involved in actin stress fiber dissolution and mediation of programmed cell death in a kinase-independent manner. Depletion of SLK by small interfering RNAs has shown that SLK is required for progression through G2 phase and a functional role for SLK during muscle development as well as in adult skeletal muscle has been suggested.
SLK is highly expressed in the muscle mass and neuronal lineages of developing embryos. The protein can be detected at E10.5 and E12.5 in the forebrain, midbrain and hindbrain of the developing CNS. At later developmental stages, it is expressed in the hypothalamus region, all layers of the neural tube, dorsal root ganglion and in the proliferating ependymal layers. Following middle cerebral artery occlusion, SLK expressing neuronal cells are lost and SLK is localized to phagocytic macrophages.
In adult muscle tissue, SLK is found at myofibrillar striations of specific subsets of myofibers. In addition it is highly expressed in the nerve at neuromuscular junctions as well as in tubular epithelial cells, in fetal and adult kidneys and in developing and mature podocytes. SLK activity is increased during the G2 phase, after incubation with serum or after exposure to chemical anoxia whereas SLK expression is decreased in quiescent and differentiating cells. SLK resides in the cytoplasm and co-localises with the mitotic spindle during mitosis.
SLK is cleaved by caspase 3 in vitro and in vivo during c-Myc-, tumor necrosis factor alpha, and UV-induced apoptosis. Cleavage of SLK results in two domains with distinct activities: an activated N-terminal kinase domain that promotes apoptosis and cytoskeletal rearrangements and a C-terminal domain that disassembles actin stress fibers. SLK has been reported to interact with the neuronal transmembrane protein calsyntenin and has been reported to phosphorylate Polo-like kinase 1.
SLK has been identified as marker for Cutaneous T-cell lymphomas (CTCL), which are a group of skin neoplasms that originate from T lymphocytes predominantly and include mycosis fungoides (MF) and the Sezary Syndrome (SS). In addition, SLK is induced during recovery from acute renal failure and has been suggested to be involved in the pathogenesis of podocyte-specific glomerulopathies like membranous nephropathy. Here we determined the structure of unphosphorylated SLK1 in complex with the inhibitor 5-amino-3- ((4-(aminosulfonyl) phenyl) amino)-N-(2,6- difluorophenyl) 1,2,4-triazole -1-carbothioamide as well as the structure of mono-phosphorylated SLK1 in complex with a pyrazol quinazoline inhibitor. Both structures revealed a flipped out activation segment conformation binding to the substrate binding site of a symmetry related molecule.
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