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 (1)

1 Wellcome Trust Biocentre, Division of Biological Chemistry & Molecular Biology

TAB1 (TAK1-binding protein 1) is one of the regulatory subunits of TGF{beta}-activated kinase 1 (TAK1), a protein kinase that lies at the head of three pro-inflammatory kinase cascades. Here we report the crystal structure of the N-terminal domain of TAB1. Surprisingly, TAB1 possesses a fold closely related to that of the PPM phosphatase family as demonstrated by the close structural similarity with protein phosphatase 2C{alpha}. However, we were unable to detect any phosphatase activity for TAB1 using a phosphopeptide or p-nitrophenyl phosphate as substrates. Although the overall protein phosphatase 2C{alpha} 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.

Mots clés: Life Sciences

Sarah H Conner, Gursant Kular, Mark Peggie, Sharon Shepherd, Alexander W Schüttelkopf, et al.. TAK1-binding protein 1 is a pseudophosphatase. Biochemical Journal, 2006, 399 (3), pp.427-434. ⟨10.1042/BJ20061077⟩. ⟨hal-00478633⟩