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Science 326 (5960): 1707-1711

Copyright © 2009 by the American Association for the Advancement of Science

Structure of the LKB1-STRAD-MO25 Complex Reveals an Allosteric Mechanism of Kinase Activation

Elton Zeqiraj,1,2 Beatrice Maria Filippi,2 Maria Deak,2 Dario R. Alessi,2 Daan M. F. van Aalten1,*

Abstract: The LKB1 tumor suppressor is a protein kinase that controls the activity of adenosine monophosphate–activated protein kinase (AMPK). LKB1 activity is regulated by the pseudokinase STRAD{alpha} and the scaffolding protein MO25{alpha} through an unknown, phosphorylation-independent, mechanism. We describe the structure of the core heterotrimeric LKB1-STRAD{alpha}-MO25{alpha} complex, revealing an unusual allosteric mechanism of LKB1 activation. STRAD{alpha} adopts a closed conformation typical of active protein kinases and binds LKB1 as a pseudosubstrate. STRAD{alpha} and MO25{alpha} promote the active conformation of LKB1, which is stabilized by MO25{alpha} 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 in various sporadic cancers impair LKB1 function.

1 Division of Molecular Microbiology, 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.

* To whom correspondence should be addressed. E-mail: dmfvanaalten{at}dundee.ac.uk

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