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)