Systematic discovery of linear binding motifs targeting an ancient protein interaction surface on MAP kinases
| Autor: | András Zeke, Attila Reményi, Zsuzsanna Dosztányi, Bálint Mészáros, Olga V. Kalinina, Klára Kirsch, Anita Alexa, Tomas Bastys, Ágnes Garai |
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| Rok vydání: | 2015 |
| Předmět: |
Cell signaling
Surface Properties In silico Sequence alignment General Biochemistry Genetics and Molecular Biology Article Protein–protein interaction Structural Biology Human proteome project Animals Humans Amino Acid Sequence Binding selectivity General Immunology and Microbiology biology Applied Mathematics Computational Biology Articles Cell biology Protein Structure Tertiary Protein kinase binding Molecular Docking Simulation protein–protein interaction Computational Theory and Mathematics Mitogen-activated protein kinase biology.protein MAP kinase cellular signaling linear motif Mitogen-Activated Protein Kinases General Agricultural and Biological Sciences Sequence Alignment Information Systems Signal Transduction |
| Zdroj: | Molecular Systems Biology ResearcherID |
| ISSN: | 1744-4292 |
| Popis: | Mitogen‐activated protein kinases (MAPK) are broadly used regulators of cellular signaling. However, how these enzymes can be involved in such a broad spectrum of physiological functions is not understood. Systematic discovery of MAPK networks both experimentally and in silico has been hindered because MAPKs bind to other proteins with low affinity and mostly in less‐characterized disordered regions. We used a structurally consistent model on kinase‐docking motif interactions to facilitate the discovery of short functional sites in the structurally flexible and functionally under‐explored part of the human proteome and applied experimental tools specifically tailored to detect low‐affinity protein–protein interactions for their validation in vitro and in cell‐based assays. The combined computational and experimental approach enabled the identification of many novel MAPK‐docking motifs that were elusive for other large‐scale protein–protein interaction screens. The analysis produced an extensive list of independently evolved linear binding motifs from a functionally diverse set of proteins. These all target, with characteristic binding specificity, an ancient protein interaction surface on evolutionarily related but physiologically clearly distinct three MAPKs (JNK, ERK, and p38). This inventory of human protein kinase binding sites was compared with that of other organisms to examine how kinase‐mediated partnerships evolved over time. The analysis suggests that most human MAPK‐binding motifs are surprisingly new evolutionarily inventions and newly found links highlight (previously hidden) roles of MAPKs. We propose that short MAPK‐binding stretches are created in disordered protein segments through a variety of ways and they represent a major resource for ancient signaling enzymes to acquire new regulatory roles. |
| Databáze: | OpenAIRE |
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