Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation

Elton Zeqiraj, Beatrice Maria Filippi, Maria Deak, Dario R. Alessi, Daan M. F. van Aalten (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    184 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1707-1711
    Number of pages5
    JournalScience
    Volume326
    Issue number5960
    Early online date5 Nov 2009
    DOIs
    Publication statusPublished - 18 Dec 2009

    Keywords

    • Dependent protein kinase
    • LKB1
    • STRAD

    Cite this

    Zeqiraj, Elton ; Filippi, Beatrice Maria ; Deak, Maria ; Alessi, Dario R. ; van Aalten, Daan M. F. / Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. In: Science. 2009 ; Vol. 326, No. 5960. pp. 1707-1711.
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    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.",
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    Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. / Zeqiraj, Elton; Filippi, Beatrice Maria; Deak, Maria; Alessi, Dario R.; van Aalten, Daan M. F. (Lead / Corresponding author).

    In: Science, Vol. 326, No. 5960, 18.12.2009, p. 1707-1711.

    Research output: Contribution to journalArticle

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