Submitted on June 29, 2009
Accepted on October 20, 2009
Structure of the LKB1-STRAD-MO25 Complex Reveals an Allosteric Mechanism of Kinase Activation
Elton Zeqiraj 1, Beatrice Maria Filippi 2, Maria Deak 2, Dario R. Alessi 2, Daan M. F. van Aalten 3*
1 Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.; MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
2 MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
3 Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
* To whom correspondence should be addressed.
Daan M. F. van Aalten , E-mail: dmfvanaalten{at}dundee.ac.uk
The LKB1 tumor suppressor is a protein kinase that controls activity of adenine monophosphate-activated protein kinase (AMPK). LKB1 activity is regulated by the pseudokinase STRAD
and the scaffolding protein MO25, through an unknown, phosphorylation-independent mechanism. We describe the structure of the core heterotrimeric LKB1-STRAD-MO25 complex, revealing an unusual allosteric mechanism of LKB1 activation. STRAD adopts a closed conformation typical of active protein kinases and binds LKB1 as a pseudosubstrate. STRAD and MO25 promote the active conformation of LKB1, which is stabilised by MO25 interacting with the LKB1 activation loop. This previously undescribed mechanism of kinase activation may be relevant to understanding the evolution of other pseudokinases. The structure also reveals how mutations found in Peutz-Jeghers syndrome and other cancers impair LKB1 function.
