Journal
STRUCTURE
Volume 15, Issue 10, Pages 1215-1226Publisher
CELL PRESS
DOI: 10.1016/j.str.2007.08.011
Keywords
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Funding
- NHLBI NIH HHS [R01 HL-65978-5, R01 HL065978, P01HL070295-6, P01 HL070295] Funding Source: Medline
- NIGMS NIH HHS [R01GM079498, R01 GM079498] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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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 similar to 0.2 mu m) 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 auto phosphorylation 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.
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