Mouse protein 25 (MO25) is a 40-kDa protein that, together with the STE20-related adaptor- (STRAD) 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). MO25 binds directly to a conserved Trp-Glu-Phe sequence at the STRAD C terminus, markedly enhancing binding of STRAD to LKB1 and increasing LKB1 catalytic activity. The MO25 crystal structure reveals a helical repeat fold, distantly related to the Armadillo proteins. A complex with the STRAD 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 MO25 is a scaffold protein to which other regions of STRAD-LKB1, cellular LKB1 substrates or regulatory components could bind.
- Protein kinase