Crystal structure of MO25 in complex with the C terminus of the pseudo kinase STE20-related adaptor

TY - JOUR

T1 - Crystal structure of MO25 in complex with the C terminus of the pseudo kinase STE20-related adaptor

AU - Milburn, Christine C.

AU - Boudeau, Jerome

AU - Deak, Maria

AU - Alessi, Dario R.

AU - van Aalten, Daan M. F.

N1 - dc.publisher: Nature Publishing Group

PY - 2004

Y1 - 2004

N2 - 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.

AB - 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.

KW - Protein kinase

U2 - 10.1038/nsmb716

DO - 10.1038/nsmb716

M3 - Article

SN - 1545-9993

VL - 11

SP - 193

EP - 200

JO - Nature Structural & Molecular Biology

JF - Nature Structural & Molecular Biology

IS - 2

ER -