Orchestrating serine/threonine phosphorylation and elucidating downstream effects by short linear motifs.

Johanna Kliche,Ylva Ivarsson

doi:10.1042/bcj20200714

Abstract

Cellular function is based on protein–protein interactions. A large proportion of these interactions involves the binding of short linear motifs (SLiMs) by folded globular domains. These interactions are regulated by post-translational modifications, such as phosphorylation, that create and break motif binding sites or tune the affinity of the interactions. In addition, motif-based interactions are involved in targeting serine/threonine kinases and phosphatases to their substrate and contribute to the specificity of the enzymatic actions regulating which sites are phosphorylated. Here, we review how SLiM-based interactions assist in determining the specificity of serine/threonine kinases and phosphatases, and how phosphorylation, in turn, affects motif-based interactions. We provide examples of SLiM-based interactions that are turned on/off, or are tuned by serine/threonine phosphorylation and exemplify how this affects SLiM-based protein complex formation.

Highlights

Cellular function relies on interactions between globular domains and short linear motifs (SLiMs) that are commonly found in the intrinsically disordered regions of the proteome [1]
We focus on the docking motifs that contribute to the targeting of serine/threonine kinases and phosphatases (Figure 1B,D) to their substrates, and the effects of phosphorylation on SLiM-based interactions (Figure 1C)
mitogen-activated protein kinases (MAPKs) play a central role in the transfer of extracellular signals to intracellular responses [20] and phosphorylate a wide range of substrates, with distinct specificities exhibited by different family members

Summary

Johanna Kliche and Ylva Ivarsson

A large proportion of these interactions involves the binding of short linear motifs (SLiMs) by folded globular domains. These interactions are regulated by post-translational modifications, such as phosphorylation, that create and break motif binding sites or tune the affinity of the interactions. Motif-based interactions are involved in targeting serine/threonine kinases and phosphatases to their substrate and contribute to the specificity of the enzymatic actions regulating which sites are phosphorylated. We review how SLiM-based interactions assist in determining the specificity of serine/threonine kinases and phosphatases, and how phosphorylation, in turn, affects motif-based interactions. We provide examples of SLiM-based interactions that are turned on/off, or are tuned by serine/threonine phosphorylation and exemplify how this affects SLiM-based protein complex formation.

Introduction

Docking motifs of MAPKs

Examples of docking motifs binding to individual kinases

Docking motifs of cyclins

The readers of the phosphorylation code