Systematic discovery of linear binding motifs targeting an ancient protein interaction surface on MAP kinases

András Zeke, Tomas Bastys, Anita Alexa, Ágnes Garai, Bálint Mészáros, Klára Kirsch, Z. Dosztányi, Olga V. Kalinina, A. Reményi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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. Synopsis The disordered part of the human proteome contains a large number of short linear motif occurrences that can bind to MAP kinases. These simple protein-protein recruitment sites represent a major resource for ancient signaling enzymes to acquire new regulatory roles.

Original languageEnglish
Article number837
JournalMolecular systems biology [electronic resource].
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Fingerprint

Protein Kinase
Protein Transport
mitogen-activated protein kinase
Membrane Proteins
Phosphotransferases
Proteins
Protein
Mitogen-Activated Protein Kinases
Interaction
Enzymes
proteins
Docking
Protein-protein Interaction
Protein Binding
Affine transformation
protein-protein interactions
proteome
Proteome
phosphotransferases (kinases)
Resources

Keywords

  • cellular signaling
  • linear motif
  • MAP kinase
  • protein-protein interaction

ASJC Scopus subject areas

  • Applied Mathematics
  • Information Systems
  • Computational Theory and Mathematics
  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)

Cite this

Systematic discovery of linear binding motifs targeting an ancient protein interaction surface on MAP kinases. / Zeke, András; Bastys, Tomas; Alexa, Anita; Garai, Ágnes; Mészáros, Bálint; Kirsch, Klára; Dosztányi, Z.; Kalinina, Olga V.; Reményi, A.

In: Molecular systems biology [electronic resource]., Vol. 11, No. 11, 837, 01.11.2015.

Research output: Contribution to journalArticle

Zeke, András ; Bastys, Tomas ; Alexa, Anita ; Garai, Ágnes ; Mészáros, Bálint ; Kirsch, Klára ; Dosztányi, Z. ; Kalinina, Olga V. ; Reményi, A. / Systematic discovery of linear binding motifs targeting an ancient protein interaction surface on MAP kinases. In: Molecular systems biology [electronic resource]. 2015 ; Vol. 11, No. 11.
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