Crystal structure of MO25α in complex with the C terminus of the pseudo kinase STE20-related adaptor

Mouse protein 25alpha (MO25alpha) is a 40-kDa protein that, together with the STE20-related adaptor-alpha (STRADalpha) pseudo kinase, forms a regulatory complex capable of stimulating the activity of the LKB1 tumor suppressor protein kinase. The latter is mutated in the inherited Peutz-Jeghers cancer syndrome (PJS). MO25alpha binds directly to a conserved Trp-Glu-Phe sequence at the STRADalpha C terminus, markedly enhancing binding of STRADalpha to LKB1 and increasing LKB1 catalytic activity. The MO25alpha crystal structure reveals a helical repeat fold, distantly related to the Armadillo proteins. A complex with the STRADalpha peptide reveals a hydrophobic pocket that is involved in a unique and specific interaction with the Trp-Glu-Phe motif, further supported by mutagenesis studies. The data represent a first step toward structural analysis of the LKB1-STRAD-MO25 complex, and suggests that MO25alpha is a scaffold protein to which other regions of STRAD-LKB1, cellular LKB1 substrates or regulatory components could bind.