Crystal structure of MO25 alpha in complex with the C terminus of the pseudo kinase STE20-related adaptor.
Mouse protein 25 alpha (MO25 alpha) is a 40-kDa protein that, together with the STE20-related adaptor-alpha (STRAD alpha) 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 alpha binds directly to a conserved Trp-Glu-Phe sequence at the STRAD alpha C terminus, markedly enhancing binding of STRAD alpha to LKB1 and increasing LKB1 catalytic activity. The MO25 alpha crystal structure reveals a helical repeat fold, distantly related to the Armadillo proteins. A complex with the STRAD alpha 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 alpha is a scaffold protein to which other regions of STRAD-LKB1, cellular LKB1 substrates or regulatory components could bind.
Milburn
Christine C
CC
Division of Biological Chemistry & Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
Boudeau
Jérôme
J
Deak
Maria
M
Alessi
Dario R
DR
van Aalten
Daan M F
DM
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D017931:DNA Primers; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C000629659:Cab39 protein, mouse; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D017931:DNA Primers; C476400:STRADA protein, human