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

Content Provider	PubMed Central
Author	Jauch, Ralf Cho, Min-kyu Stefan, Jäkel Netter, Catharina Schreiter, Kay Aicher, Babette Markus, Zweckstetter Herbert, Jäckle Wahl, Markus C.
Copyright Year	2006
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 Mnk2D228G–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.
Related Links	http://dx.doi.org/10.1038/sj.emboj.7601285
Ending Page	4032
Page Count	13
Starting Page	4020
File Format	PDF
ISSN	02614189
e-ISSN	14602075
Journal	The EMBO Journal
Issue Number	17
Volume Number	25
Language	English
Publisher Date	2006-09-06
Access Restriction	Open
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Immunology and Microbiology(all) Neuroscience(all) Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Microbiology Medicine Molecular Biology

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