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

Abstract

Mouse protein 25α (MO25α) is a 40-kDa protein that, together with the STE20-related adaptor-α (STRADα) 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). MO25α binds directly to a conserved Trp-Glu-Phe sequence at the STRADα C terminus, markedly enhancing binding of STRADα to LKB1 and increasing LKB1 catalytic activity. The MO25α crystal structure reveals a helical repeat fold, distantly related to the Armadillo proteins. A complex with the STRADα 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 MO25α is a scaffold protein to which other regions of STRAD–LKB1, cellular LKB1 substrates or regulatory components could bind.

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Figure 1: Stereo ribbon drawing of the MO25α–peptide complex structure, showing the two N-terminal helices followed by six repeats of three helices each.
Figure 2: Repeat structure.
Figure 3: Electrostatic potential of the surfaces of (from left to right) MO25α, PUM1, β-catenin and importin-α made with GRASP53.
Figure 4: Binding of the STRAD peptide.
Figure 5: Mutagenesis of the STRAD peptide-binding site.

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Acknowledgements

We thank the European Synchrotron Radiation Facility (Grenoble, France) for the time at beamlines ID14-EH4. C.C.M. is supported by a Biotechnology and Biological Sciences Research Council CASE studentship, D.M.F.v.A. by a Wellcome Trust Career Development Research Fellowship and an European Molecular Biology Organization Young Investigator Fellowship, D.R.A. by the Medical Research Council (UK), Diabetes UK, Association for International Cancer Research. D.M.F.v.A. and D.R.A. are also supported by the pharmaceutical companies supporting the Division of Signal Transduction Therapy unit in Dundee (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck & Co. Inc, Merck KGA and Pfizer).

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Correspondence to Daan M F van Aalten.

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Milburn, C., Boudeau, J., Deak, M. et al. Crystal structure of MO25α in complex with the C terminus of the pseudo kinase STE20-related adaptor. Nat Struct Mol Biol 11, 193–200 (2004). https://doi.org/10.1038/nsmb716

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