TAB1 [TAK1 (transforming growth factor-β-activated kinase 1)-binding protein 1] is one of the regulatory subunits of TAK1, a protein kinase that lies at the head of three pro-inflammatory kinase cascades. In the current study we report the crystal structure of the N-terminal domain of TAB1. Surprisingly, TAB1 possesses a fold closely related to that of the PPM (Mg2+- or Mn2+-dependent protein phosphatase) family as demonstrated by the close structural similarity with protein phosphatase 2Cα. However, we were unable to detect any phosphatase activity for TAB1 using a phosphopeptide or p-nitrophenyl phosphate as substrate. Although the overall protein phosphatase 2Cα fold is conserved in TAB1, detailed structural analyses and mutagenesis studies show that several key residues required for dual metal-binding and catalysis are not present in TAB1, although binding of a single metal is supported by soaking experiments with manganese and isothermal titration calorimetry. Thus, it appears that TAB1 is a ‘pseudophosphatase’, possibly binding to and regulating accessibility of phosphorylated residues on substrates downstream of TAK1 or on the TAK1 complex itself.
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Research Article|
October 13 2006
TAK1-binding protein 1 is a pseudophosphatase
Sarah H. Conner;
Sarah H. Conner
1
*MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Gursant Kular;
Gursant Kular
1
*MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Mark Peggie;
Mark Peggie
1
*MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Sharon Shepherd;
Sharon Shepherd
1
†Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Alexander W. Schüttelkopf;
Alexander W. Schüttelkopf
†Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Philip Cohen;
Philip Cohen
*MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Daan M. F. Van Aalten
Daan M. F. Van Aalten
2
†Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
2To whom correspondence should be addressed (email dava@davapc1.bioch.dundee.ac.uk).
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Publisher: Portland Press Ltd
Received:
July 14 2006
Accepted:
August 01 2006
Accepted Manuscript online:
August 01 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 399 (3): 427–434.
Article history
Received:
July 14 2006
Accepted:
August 01 2006
Accepted Manuscript online:
August 01 2006
Citation
Sarah H. Conner, Gursant Kular, Mark Peggie, Sharon Shepherd, Alexander W. Schüttelkopf, Philip Cohen, Daan M. F. Van Aalten; TAK1-binding protein 1 is a pseudophosphatase. Biochem J 1 November 2006; 399 (3): 427–434. doi: https://doi.org/10.1042/BJ20061077
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