Structural basis for CRM1 nuclear export complex assembly

Abstract

The LKB1 tumor suppressor kinase regulates activity of the AMPK family of kinases. LKB1 is activaty is regulated by the pseudokinase STRADa and the scaffolding protein MO25a through an unknown, phosphorylation-independent, mechanism. Here we describe the 2.65 Å structure of the heterotrimeric LKB1/STRADa/MO25a complex, revealing an unusual allosteric mechanism of LKB1 activation. STRADa adopts a closed conformation typical of active protein kinases, and binds LKB1 as a pseudosubstrate. STRADa binding, promotes the active conformation of LKB1, which is further stabilized by MO25a interacting with the LKB1 activation loop. This represents a previously undescribed mechanism of kinase activation that 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. The body text font is Times New Roman (size 9) with single spacing and full justification. The total allowed area is 8 x 24 cm.