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EMBO J. 2006 Sep 6;25(17):4020-32. Epub 2006 Aug 17.

Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment.

Author information

1
Max-Planck-Institut für Biophysikalische Chemie, Abteilung Molekulare Entwicklungsbiologie, Göttingen, Germany. jauchr@gis.a-star.edu.sg

Abstract

Autoinhibition is a recurring mode of protein kinase regulation and can be based on diverse molecular mechanisms. Here, we show by crystal structure analysis, nuclear magnetic resonance (NMR)-based nucleotide affinity studies and rational mutagenesis that nonphosphorylated mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1 is autoinhibited by conversion of the activation segment into an autoinhibitory module. In a Mnk1 crystal structure, the activation segment is repositioned via a Mnk-specific sequence insertion at the N-terminal lobe with the following consequences: (i) the peptide substrate binding site is deconstructed, (ii) the interlobal cleft is narrowed, (iii) an essential Lys-Glu pair is disrupted and (iv) the magnesium-binding loop is locked into an ATP-competitive conformation. Consistently, deletion of the Mnk-specific insertion or removal of a conserved phenylalanine side chain, which induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1. Structural rearrangements required for the activation of Mnks are apparent from the cocrystal structure of a Mnk2 D228G -staurosporine complex and can be modeled on the basis of crystal packing interactions. Our data suggest a novel regulatory mechanism specific for the Mnk subfamily.

PMID:
16917500
PMCID:
PMC1560367
DOI:
10.1038/sj.emboj.7601285
[Indexed for MEDLINE]
Free PMC Article

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