Peutz-Jeghers cancer syndrome (PJS) related protein Mo25 Alpha in Complex with the C-Terminus of the Pseudo Kinase STE-20 Related Adaptor
Homo sapiens (human)
Peutz-Jeghers cancer syndrome (PJS) is an autosomal-dominant inherited disorder which results in the development of multiple gastrointestinal hamartomas and a predisposition to the development of benign and malignant tumors. LKB1, a Ser/Thr protein kinase, is a tumor suppressor protein kinase and participates in G1 cell cycle arrest. LKB1 in PJS patients is mutated with concomitant reduction of catalytic activity. Recently it has been discovered that the LKB1 catalytic activity increases when LKB1 binds to certain proteins called STRAD-alpha and MO25-alpha. STRAD-alpha has a STE20-like protein kinase domain but lacks two important motifs, the VIb and VII subdomains in the catalytic domain which are indispensable for catalytic activity. This protein is catalytically inactive and has therefore been classified as a pseudo kinase. MO25 (mouse protein 25)-alpha-related proteins include well conserved residues but their structural folds have not been determined. In this complex, STRAD-alpha and MO25-alpha play essential roles in recognizing and phosphorylating a substrate for LKB1 by LKB1. The binding of STRAD-alpha to LKB1 enhances its catalytic activity about four-fold and, moreover, in the presence of MO25-alpha this activity is increased more than 50-fold. In addition, MO25-alpha induces STRAD-alpha to bind to LKB1, and by cooperating with STRAD-alpha, leads LKB1 to anchor in the cytoplasm and suppress cell growth.
The structure of the complex of MO25-alpha and STRAD-alpha has been determined. This complex structure shows that MO25-alpha has a helical repeat fold constructed of only alpha-helices, and a deep hydrophobic pocket. In this pocket, MO25-alpha interacts with the conserved Trp-Glu-Phe motif found at the STRAD-alpha C-terminus. The crystal analysis of this complex represents a first step toward the structure analysis of the LKB1-STRAD-MO25 complex. Moreover it has been suggested that MO25-alpha functions as a scaffold protein to which in the LKB1-STRAD complex, LKB1 substrates or regulatory components bind.
Protein Data Bank (PDB)
author: Yuko Tsuchiya