Modular evolution of phosphorylation-based signalling systems

Philosophical Transactions of the Royal Society B: Biological Sciences, Sep 2012

Phosphorylation sites are formed by protein kinases (‘writers’), frequently exert their effects following recognition by phospho-binding proteins (‘readers’) and are removed by protein phosphatases (‘erasers’). This writer–reader–eraser toolkit allows phosphorylation events to control a broad range of regulatory processes, and has been pivotal in the evolution of new functions required for the development of multi-cellular animals. The proteins that comprise this system of protein kinases, phospho-binding targets and phosphatases are typically modular in organization, in the sense that they are composed of multiple globular domains and smaller peptide motifs with binding or catalytic properties. The linkage of these binding and catalytic modules in new ways through genetic recombination, and the selection of particular domain combinations, has promoted the evolution of novel, biologically useful processes. Conversely, the joining of domains in aberrant combinations can subvert cell signalling and be causative in diseases such as cancer. Major inventions such as phosphotyrosine (pTyr)-mediated signalling that flourished in the first multi-cellular animals and their immediate predecessors resulted from stepwise evolutionary progression. This involved changes in the binding properties of interaction domains such as SH2 and their linkage to new domain types, and alterations in the catalytic specificities of kinases and phosphatases. This review will focus on the modular aspects of signalling networks and the mechanism by which they may have evolved.

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Modular evolution of phosphorylation-based signalling systems

Jing Jin 1 2 Tony Pawson 0 1 2 0 Department of Molecular Genetics, University of Toronto , Toronto, Ontario , Canada M5S 1A8 1 One contribution of 13 to a Theme Issue 'The evolution of protein phosphorylation' 2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue , Toronto, Ontario , Canada M5G 1X5 Phosphorylation sites are formed by protein kinases ('writers'), frequently exert their effects following recognition by phospho-binding proteins ('readers') and are removed by protein phosphatases ('erasers'). This writer - reader - eraser toolkit allows phosphorylation events to control a broad range of regulatory processes, and has been pivotal in the evolution of new functions required for the development of multi-cellular animals. The proteins that comprise this system of protein kinases, phospho-binding targets and phosphatases are typically modular in organization, in the sense that they are composed of multiple globular domains and smaller peptide motifs with binding or catalytic properties. The linkage of these binding and catalytic modules in new ways through genetic recombination, and the selection of particular domain combinations, has promoted the evolution of novel, biologically useful processes. Conversely, the joining of domains in aberrant combinations can subvert cell signalling and be causative in diseases such as cancer. Major inventions such as phosphotyrosine (pTyr)-mediated signalling that flourished in the first multi-cellular animals and their immediate predecessors resulted from stepwise evolutionary progression. This involved changes in the binding properties of interaction domains such as SH2 and their linkage to new domain types, and alterations in the catalytic specificities of kinases and phosphatases. This review will focus on the modular aspects of signalling networks and the mechanism by which they may have evolved. 1. INTRODUCTION: A WRITER READER ERASER TOOLKIT FOR PHOSPHORYLATION A driving force in the evolution of single-celled organisms to metazoan species has been the adaptation of reversible protein phosphorylation to allow for increasingly complex modes of intercellular communication [1,2]. Unlike many other forms of post-translational modification (PTM)for example, methylation, acetylation and ubiquitylation, phosphorylation on a single residue is unitary, as only one phosphate can be added to an acceptor amino acid. Protein phosphorylation in eukaryotes occurs primarily on the hydroxyamino acids serine, threonine and tyrosine, and also infrequently on histidines and cysteines [3], as well as on lysines and arginines [4]. Most bacteria have phosphotransferase systems that phosphorylate histidine, aspartate, glutamate and cysteine residues [5], and also encode proteins with a protein-kinase-like fold [6] that probably gave rise to the eukaryotic protein kinases (ePKs) [7]. There is also a distinct class of bacterial tyrosine kinases (TKs) [8], but these are not directly related to the eukaryotic TKs that only appeared later in the tree of life. Here, we will focus on aspects of serine/threonine and tyrosine phosphorylation, and the recognition of phosphosites, in eukaryotic evolution. Protein phosphorylation and the resulting cellular response commonly require a three-part toolkit in which the kinases that phosphorylate substrate proteins can be viewed as writers, phosphatases that dephosphorylate phosphoproteins act as erasers and modular protein domains that recognize phosphorylated motifs to deliver a downstream signal function as readers (figure 1a) [9]. In eukaryotes, the writers are principally composed of serine/threonine kinases (STKs), TKs, and dual-specificity kinases (DSKs), which are similar to STKs but can phosphorylate tyrosine as well as serine/threonine. The catalytic domains of these kinases are related in primary sequence and share a common structural fold [10,11]. Phosphoserine and phosphothreonine (pSer/pThr) sites are primarily dephosphorylated by members of the phosphoprotein phosphatase (PPP) family, which includes PP1, PP2A, PP2B and PP4 7 in human cells, and the metallo-dependent protein phosphatase (PPM) family (as represented by PP2C) [12]. The PPP and PPM families are unrelated in sequence and probably evolved from two unique ancestral genes (figure 1b), but remarkably have converged to possess highly related O O P O O structures at their catalytic centres [13]. The principal protein-tyrosine phosphatase (PTP) family is different yet again; although its members share a common class of catalytic domain [14], they are very diverse in their substrate preferences, with some family enzymes being known to dephosphorylate non-protein targets, including carbohydrate, mRNA and phosphoinositides [15,16]. One means by which phosphorylation can modify a proteins function is to induce a conformational change (allostery), which in the case of enzymes can lead to altered catalytic activity. Protein kinases themselves p (...truncated)


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Jing Jin, Tony Pawson. Modular evolution of phosphorylation-based signalling systems, Philosophical Transactions of the Royal Society B: Biological Sciences, 2012, pp. 2540-2555, 367/1602, DOI: 10.1098/rstb.2012.0106