A PEF/Y substrate recognition and signature motif plays a critical role in DAPK-related kinase activity
العنوان: | A PEF/Y substrate recognition and signature motif plays a critical role in DAPK-related kinase activity |
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المؤلفون: | Xun Li, Vivian Pogenberg, Iñaki de Diego, Koen Temmerman, Matthias Wilmanns, Bertrand Simon, Weronika Jonko |
المساهمون: | European Commission, Ministerio de Ciencia e Innovación (España), European Molecular Biology Laboratory |
المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname |
بيانات النشر: | Cell Press, 2014. |
سنة النشر: | 2014 |
مصطلحات موضوعية: | Molecular Sequence Data, Clinical Biochemistry, Mitogen-activated protein kinase kinase, Crystallography, X-Ray, Biochemistry, SH3 domain, MAP2K7, Substrate Specificity, Drug Discovery, Humans, c-Raf, Amino Acid Sequence, Kinase activity, Protein kinase A, Molecular Biology, Pharmacology, Binding Sites, biology, MAP kinase kinase kinase, Cyclin-dependent kinase 2, General Medicine, Protein Structure, Tertiary, Molecular Docking Simulation, Death-Associated Protein Kinases, HEK293 Cells, Amino Acid Substitution, biology.protein, Molecular Medicine, Peptides, Sequence Alignment |
الوصف: | Knowledge about protein kinase substrate preferences is biased toward residues immediately adjacent to the site of phosphorylation. By a combined structural, biochemical, and cellular approach, we have discovered an unexpected substrate recognition element with the consensus sequence PEF/Y in the tumor suppressor death-associated protein kinase 1. This motif can be effectively blocked by a specific pseudosubstrate-type interaction with an autoregulatory domain of this kinase. In this arrangement, the central PEF/Y glutamate interacts with a conserved arginine distant to the phosphorylation site in sequence and structure. We also demonstrate that the element is crucial for kinase activity regulation and substrate recognition. The PEF/Y motif distinguishes close death-associated protein kinase relatives from canonical calcium/calmodulin-dependent protein kinases. Insight into this signature and mode of action offers new opportunities to identify specific small molecule inhibitors in PEF/Y-containing protein kinases. © 2014 Elsevier Ltd. All rights reserved. This work was supported by European Commission grants CAMKIN (HPRN-CT-2002- 00252) and SPINE2-COMPLEXES (LSHG-CT-2006-031220). I.d.D. was supported by a grant from the Spanish Ministry of Science and Innovation MICINN (ES-2006-0149). K.T. and X.L. were supported by an EMBL Interdisciplinary Postdoc (EIPOD) fellowship under Marie Curie Actions (COFUND) |
تدمد: | 1074-5521 |
الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fd9d2a23a0ddd62061303af98d1580d1Test http://hdl.handle.net/10261/124198Test |
حقوق: | OPEN |
رقم الانضمام: | edsair.doi.dedup.....fd9d2a23a0ddd62061303af98d1580d1 |
قاعدة البيانات: | OpenAIRE |
تدمد: | 10745521 |
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