Abstract
SummaryApoptosis signal-regulating kinase 1 (ASK1) plays an essential role in stress and immune response and has been linked to the development of several diseases. Here, we present the structure of the human ASK1 catalytic domain in complex with staurosporine. Analytical ultracentrifugation (AUC) and crystallographic analysis showed that ASK1 forms a tight dimer (Kd ∼ 0.2 μM) interacting in a head-to-tail fashion. We found that the ASK1 phosphorylation motifs differ from known ASK1 phosphorylation sites but correspond well to autophosphorylation sites identified by mass spectrometry. Reporter gene assays showed that all three identified in vitro autophosphorylation sites (Thr813, Thr838, Thr842) regulate ASK1 signaling, but site-directed mutants showed catalytic activities similar to wild-type ASK1, suggesting a regulatory mechanism independent of ASK1 kinase activity. The determined high-resolution structure of ASK1 and identified ATP mimetic inhibitors will provide a first starting point for the further development of selective inhibitors.
Highlights
Apoptosis signal-regulating kinase 1 (ASK1, called MAP3K5) is a mitogen-activated protein kinase kinase kinase (MAP3K) that plays an essential role in cellular stress and the immune response (Matsukawa et al, 2004)
ASK1 has been implicated in polyglutamine (PolyQ) diseases, which include at least nine inherited neurodegenerative disorders: Huntington’s disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), six spinocerebellar ataxias, and SCA3/ Machado-Joseph disease (MJD)
Polypeptides called PolyQ fragments accumulate as aggregates in the cytoplasm and/or nucleus and induce cellular stress that leads to neuronal cell death in an ASK1-dependent manner (Kariya et al, 2005; Nishitoh et al, 2002; Sekine et al, 2006)
Summary
Apoptosis signal-regulating kinase 1 (ASK1, called MAP3K5) is a mitogen-activated protein kinase kinase kinase (MAP3K) that plays an essential role in cellular stress and the immune response (Matsukawa et al, 2004). ASK1 has been linked to several diseases and has been discussed as a target for pharmaceutical intervention (Hashimoto et al, 2003; Harada et al, 2006). Polypeptides called PolyQ fragments accumulate as aggregates in the cytoplasm and/or nucleus and induce cellular stress that leads to neuronal cell death in an ASK1-dependent manner (Kariya et al, 2005; Nishitoh et al, 2002; Sekine et al, 2006). Activation of ASK1 by reactive oxygen species is a key mechanism for b-amyloid induced neurotoxicity in Alzheimer’s disease (Hashimoto et al, 2003; Kadowaki et al, 2005; Song et al, 2003)
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