Format

Send to

Choose Destination
Mol Syst Biol. 2015 Nov 3;11(11):837. doi: 10.15252/msb.20156269.

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

Author information

1
Lendület Protein Interaction Group, Institute of Enzymology Research Center for Natural Sciences Hungarian Academy of Sciences, Budapest, Hungary.
2
Max Planck Institute for Informatics, Saarbrücken, Germany Graduate School of Computer Science, Saarland University, Saarbrücken, Germany.
3
Institute of Enzymology Research Center for Natural Sciences Hungarian Academy of Sciences, Budapest, Hungary.
4
MTA-ELTE Lendület Bioinformatics Research Group, Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary.
5
Max Planck Institute for Informatics, Saarbrücken, Germany.
6
Lendület Protein Interaction Group, Institute of Enzymology Research Center for Natural Sciences Hungarian Academy of Sciences, Budapest, Hungary remenyi.attila@ttk.mta.hu.

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.

KEYWORDS:

MAP kinase; cellular signaling; linear motif; protein–protein interaction

PMID:
26538579
PMCID:
PMC4670726
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center