Title
Structural and functional characterization of the human protein kinase ASK1Structural and functional characterization of the human protein kinase ASK1
Author
Faculty/Department
Faculty of Sciences. Chemistry
Publication type
article
Publication
London,
Subject
Chemistry
Source (journal)
Structure. - London
Volume/pages
15(2007):10, p. 1215-1226
ISSN
0969-2126
ISI
000250235900009
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
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 (Kd not, vert, similar 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.
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