Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment
Ralf Jauch1, Min-Kyu Cho, Stefan Jäkel
1Max-Planck-Institut für Biophysikalische Chemie, Abteilung Molekulare Entwicklungsbiologie, Göttingen, Germany. jauchr@gis.a-star.edu.sg
The EMBO Journal
|August 19, 2006
Summary
Mitogen-activated protein (MAP) kinases interacting kinase 1 (Mnk1) is autoinhibited by a unique structural mechanism involving its activation segment. This regulation, specific to the Mnk subfamily, impacts substrate binding and ATP affinity.
Area of Science:
- Molecular biology
- Structural biology
- Biochemistry
Background:
- Protein kinase regulation often involves autoinhibition through diverse molecular mechanisms.
- Mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1 is a key regulator in cellular signaling pathways.
Purpose of the Study:
- To elucidate the molecular mechanism of autoinhibition in nonphosphorylated Mnk1.
- To investigate the role of a Mnk-specific sequence insertion in Mnk1 regulation.
Main Methods:
- Crystal structure analysis of Mnk1.
- Nuclear magnetic resonance (NMR)-based nucleotide affinity studies.
- Rational mutagenesis to probe regulatory elements.
Main Results:
- Nonphosphorylated Mnk1 is autoinhibited by its activation segment, repositioned by a Mnk-specific N-terminal insertion.
- This repositioning disrupts substrate binding, narrows the interlobal cleft, and locks the magnesium-binding loop into an ATP-competitive state.
- Deletion of the insertion or mutation of a key phenylalanine residue increases Mnk1's ATP affinity.
Conclusions:
- A novel autoinhibition mechanism, specific to the Mnk subfamily, has been identified.
- This mechanism involves structural rearrangements impacting substrate and nucleotide binding.
- Understanding this regulation provides insights into Mnk kinase function and potential therapeutic targeting.
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