Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment
| العنوان: | Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment |
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| المؤلفون: | Markus Zweckstetter, Herbert Jäckle, Catharina Netter, Markus C. Wahl, Min-Kyu Cho, Kay Schreiter, Babette Aicher, Stefan Jäkel, Ralf Jauch |
| المصدر: | The EMBO Journal. 25:4020-4032 |
| بيانات النشر: | Wiley, 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Models, Molecular, Protein Conformation, Phenylalanine, Molecular Sequence Data, Protein Serine-Threonine Kinases, Biology, Crystallography, X-Ray, Article, General Biochemistry, Genetics and Molecular Biology, chemistry.chemical_compound, Adenosine Triphosphate, Protein structure, Catalytic Domain, Humans, Magnesium, Amino Acid Sequence, Phosphorylation, Binding site, Protein kinase A, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, Peptide sequence, Protein-Serine-Threonine Kinases, General Immunology and Microbiology, Kinase, General Neuroscience, Intracellular Signaling Peptides and Proteins, Staurosporine, Cell biology, chemistry, Biochemistry, Mutation, Adenosine triphosphate |
| الوصف: | 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. |
| تدمد: | 1460-2075 0261-4189 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ec04efee2958f3e9133a3d64ade8fd72Test https://doi.org/10.1038/sj.emboj.7601285Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ec04efee2958f3e9133a3d64ade8fd72 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602075 02614189 |
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