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Apoptosis 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 (K(d) approximately 0.2 microM) 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.

Original publication

DOI

10.1016/j.str.2007.08.011

Type

Journal article

Journal

Structure

Publication Date

10/2007

Volume

15

Pages

1215 - 1226

Keywords

Amino Acid Sequence, Binding Sites, Catalysis, Dimerization, Enzyme Activation, Enzyme Inhibitors, Humans, MAP Kinase Kinase Kinase 5, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Conformation, Protein Structure, Tertiary, Staurosporine, Structure-Activity Relationship, Substrate Specificity