Structural and functional characterization of the human protein kinase ASK1.

Structural and functional characterization of the human protein kinase ASK1. Research Abstract Details 

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Structural and functional characterization of the human protein kinase ASK1. Abstract Text:

Gabor Bunkoczi,Eidarus Salah,Panagis Filippakopoulos,Oleg Fedorov,Susanne ,Frank Sobott,Sirlester A Parker,Haifeng Zhang,Wang Min,Benjamin E Turk,Stefan Knapp,Gabor Bunkoczi,Eidarus Salah,Panagis Filippakopoulos,Oleg Fedorov,Susanne ,Frank Sobott,Sirlester A Parker,Haifeng Zhang,Wang Min,Benjamin E Turk,Stefan Knapp,

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.

Structural and functional characterization of the human protein kinase ASK1. Publishing Authors By Initials

G Bunkoczi,E Salah,P Filippakopoulos,O Fedorov,S ,F Sobott,SA Parker,H Zhang,W Min,BE Turk,S Knapp,G Bunkoczi,E Salah,P Filippakopoulos,O Fedorov,S ,F Sobott,SA Parker,H Zhang,W Min,BE Turk,S Knapp,

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Structural and functional characterization of the human protein kinase ASK1. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Structure (London, England : 1993)

VOLUME: 15

Page Numbers: 1215-26

Journal Abbreviation: Structure

ISSN: 0969-2126

DAY: 16

MONTH: Oct

YEAR: 2007

Structural and functional characterization of the human protein kinase ASK1. Information

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LANGUAGE: eng

NlmUniqueID: 101087697

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Grant and Affiliation Information for Structural and functional characterization of the human protein kinase ASK1.

AFFILIATION: University of Oxford, Structural Genomics Consortium, Botnar Research Centre, Oxford OX3 7LD, United Kingdom.

Country: United States

AGENCY: United States NIGMS

GRANT: R01GM079498

ACRONYM: GM

MEDLINETA: Structure

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ACCESSION NUMBER: 2CLQ

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