REAL

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

Zeke, András and Bastys, Tomas and Alexa, Anita and Garai, Ágnes Szonja and Mészáros, Bálint and Kirsch, Klára and Dosztányi, Zsuzsanna and Reményi, Attila (2015) Systematic discovery of linear binding motifs targeting an ancient protein interaction surface on MAP kinases. Molecular Systems Biology, 11 (11). pp. 1-21. ISSN 1744-4292, ESSN: 1744-4292

[img]
Preview
Text
Zeke_A_et_all_2015_837.full.pdf

Download (3MB) | Preview

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.

Item Type: Article
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 04 Sep 2017 13:05
Last Modified: 04 Sep 2017 13:05
URI: http://real.mtak.hu/id/eprint/61384

Actions (login required)

View Item View Item