Milburn Christine C, Boudeau Jérôme, Deak Maria, Alessi Dario R, van Aalten Daan M F
Division of Biological Chemistry & Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
Nat Struct Mol Biol. 2004 Feb;11(2):193-200. doi: 10.1038/nsmb716. Epub 2004 Jan 18.
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.
小鼠蛋白25α（MO25α）是一种40 kDa的蛋白质，它与STE20相关衔接蛋白α（STRADα）伪激酶一起形成一种调节复合物，能够刺激LKB1肿瘤抑制蛋白激酶的活性。后者在遗传性黑斑息肉综合征（PJS）中发生突变。MO25α直接与STRADα C末端的保守色氨酸-谷氨酸-苯丙氨酸序列结合，显著增强STRADα与LKB1的结合并增加LKB1的催化活性。MO25α晶体结构揭示了一种螺旋重复折叠结构，与犰狳蛋白有远缘关系。与STRADα肽的复合物揭示了一个疏水口袋，该口袋参与了与色氨酸-谷氨酸-苯丙氨酸基序的独特且特异性的相互作用，诱变研究进一步支持了这一点。这些数据代表了对LKB1 - STRAD - MO25复合物进行结构分析的第一步，并表明MO25α是一种支架蛋白，STRAD - LKB1的其他区域、细胞LKB1底物或调节成分可能会与之结合。
