TAK1-binding protein 1 is a pseudophosphatase

Sarah H. Conner, Gursant Kular, Mark Peggie, Sharon Shepherd, Alexander W. Schüttelkopf, Philip Cohen, Daan M. F. van Aalten

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    48 Citations (Scopus)

    Abstract

    TAB1 [TAK1 (transforming growth factor-ß-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 2Ca. 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 2Ca 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 down-stream of TAK1 or on the TAK1 complex itself.

    Original languageEnglish
    Pages (from-to)427-434
    Number of pages8
    JournalBiochemical Journal
    Volume399
    Issue number3
    DOIs
    Publication statusPublished - 1 Nov 2006

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