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- Publisher Website: 10.1038/sj.emboj.7601285
- Scopus: eid_2-s2.0-33748358167
- PMID: 16917500
- WOS: WOS:000240763900010
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Article: Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment
Title | Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment |
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Authors | |
Keywords | Drug design Protein kinase regulation Mnk1 and Mnk2 Autoinhibition Mitogen-activated protein kinases interacting kinase |
Issue Date | 2006 |
Citation | EMBO Journal, 2006, v. 25, n. 17, p. 4020-4032 How to Cite? |
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. © 2006 European Molecular Biology Organization. All Rights Reserved. |
Persistent Identifier | http://hdl.handle.net/10722/253099 |
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 5.489 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Jauch, Ralf | - |
dc.contributor.author | Cho, Min Kyu | - |
dc.contributor.author | Jäkel, Stefan | - |
dc.contributor.author | Netter, Catharina | - |
dc.contributor.author | Schreiter, Kay | - |
dc.contributor.author | Aicher, Babette | - |
dc.contributor.author | Zweckstetter, Markus | - |
dc.contributor.author | Jäckle, Herbert | - |
dc.contributor.author | Wahl, Markus C. | - |
dc.date.accessioned | 2018-05-11T05:38:35Z | - |
dc.date.available | 2018-05-11T05:38:35Z | - |
dc.date.issued | 2006 | - |
dc.identifier.citation | EMBO Journal, 2006, v. 25, n. 17, p. 4020-4032 | - |
dc.identifier.issn | 0261-4189 | - |
dc.identifier.uri | http://hdl.handle.net/10722/253099 | - |
dc.description.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. © 2006 European Molecular Biology Organization. All Rights Reserved. | - |
dc.language | eng | - |
dc.relation.ispartof | EMBO Journal | - |
dc.subject | Drug design | - |
dc.subject | Protein kinase regulation | - |
dc.subject | Mnk1 and Mnk2 | - |
dc.subject | Autoinhibition | - |
dc.subject | Mitogen-activated protein kinases interacting kinase | - |
dc.title | Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1038/sj.emboj.7601285 | - |
dc.identifier.pmid | 16917500 | - |
dc.identifier.scopus | eid_2-s2.0-33748358167 | - |
dc.identifier.volume | 25 | - |
dc.identifier.issue | 17 | - |
dc.identifier.spage | 4020 | - |
dc.identifier.epage | 4032 | - |
dc.identifier.eissn | 1460-2075 | - |
dc.identifier.isi | WOS:000240763900010 | - |
dc.identifier.issnl | 0261-4189 | - |