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 language | English |
|---|---|
| Pages (from-to) | 1707-1711 |
| Number of pages | 5 |
| Journal | Science |
| Volume | 326 |
| Issue number | 5960 |
| Early online date | 5 Nov 2009 |
| DOIs | |
| Publication status | Published - 18 Dec 2009 |
Keywords
- Dependent protein kinase
- LKB1
- STRAD
Cite this
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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 journal › Article
TY - JOUR
T1 - Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation
AU - Zeqiraj, Elton
AU - Filippi, Beatrice Maria
AU - Deak, Maria
AU - Alessi, Dario R.
AU - van Aalten, Daan M. F.
PY - 2009/12/18
Y1 - 2009/12/18
N2 - 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.
AB - 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.
KW - Dependent protein kinase
KW - LKB1
KW - STRAD
UR - http://www.scopus.com/inward/record.url?scp=72949115493&partnerID=8YFLogxK
U2 - 10.1126/science.1178377
DO - 10.1126/science.1178377
M3 - Article
C2 - 19892943
VL - 326
SP - 1707
EP - 1711
JO - Science
JF - Science
SN - 0036-8075
IS - 5960
ER -