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

被引：61

作者：

Ralf Jauch ^{[6
]}

Min‐Kyu Cho ^{[1
]}

Stefan Jäkel ^{[2
]}

Catharina Netter ^{[3
]}

Kay Schreiter ^{[4
]}

Babette Aicher ^{[5
]}

Markus Zweckstetter ^{[4
]}

Herbert Jäckle ^{[4
]}

Markus C Wahl ^{[3
]}

机构：

[1] Max-Planck-Institut für Biophysikalische Chemie, Abteilung Molekulare Entwicklungsbiologie, Göttingen

[2] Genome Institute of Singapore, Laboratory for Structural Biochemistry, Singapore

[3] Max-Planck-Institut für Biophysikalische Chemie, NMR-Basierte Strukturbiologie, Göttingen

[4] DeveloGen AG, Göttingen

[5] Max-Planck-Institut für Biophysikalische Chemie, Abteilung Zelluläre Biochemie/Röntgenkristallographie, Göttingen

[6] Genome Institute of Singapore, Singapore 138672

[7] Max-Planck-Institut für Biophysikalische Chemie, Abteilung Zelluläre Biochemie/Röntgenkristallographie, 37077 Göttingen

来源：

The EMBO Journal | 2006年 / 25卷 / 17期

关键词：

Autoinhibition; Drug design; Mitogen-activated protein kinases interacting kinase; Mnk1 and Mnk2; Protein kinase regulation;

D O I：

10.1038/sj.emboj.7601285

中图分类号：

学科分类号：

摘要：

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. © 2006 European Molecular Biology Organization. All Rights Reserved.

引用

页码：4020 / 4032

页数：12

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