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Review
. 2012 Sep 19;367(1602):2556-73.
doi: 10.1098/rstb.2012.0107.

Evolution of SH2 domains and phosphotyrosine signalling networks

Bernard A Liu  1 , Piers D Nash
Affiliations
Review

Evolution of SH2 domains and phosphotyrosine signalling networks

Bernard A Liu et al. Philos Trans R Soc Lond B Biol Sci. .

Abstract

Src homology 2 (SH2) domains mediate selective protein-protein interactions with tyrosine phosphorylated proteins, and in doing so define specificity of phosphotyrosine (pTyr) signalling networks. SH2 domains and protein-tyrosine phosphatases expand alongside protein-tyrosine kinases (PTKs) to coordinate cellular and organismal complexity in the evolution of the unikont branch of the eukaryotes. Examination of conserved families of PTKs and SH2 domain proteins provides fiduciary marks that trace the evolutionary landscape for the development of complex cellular systems in the proto-metazoan and metazoan lineages. The evolutionary provenance of conserved SH2 and PTK families reveals the mechanisms by which diversity is achieved through adaptations in tissue-specific gene transcription, altered ligand binding, insertions of linear motifs and the gain or loss of domains following gene duplication. We discuss mechanisms by which pTyr-mediated signalling networks evolve through the development of novel and expanded families of SH2 domain proteins and the elaboration of connections between pTyr-signalling proteins. These changes underlie the variety of general and specific signalling networks that give rise to tissue-specific functions and increasingly complex developmental programmes. Examination of SH2 domains from an evolutionary perspective provides insight into the process by which evolutionary expansion and modification of molecular protein interaction domain proteins permits the development of novel protein-interaction networks and accommodates adaptation of signalling networks.

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Figures

Figure 1.
Figure 1.
The phosphotyrosine signalling circuitry expands in unikonts to become a large and complex signalling system in mammals. (a) The number of writers (protein-tyrosine kinases, PTKs), erasers (protein-tyrosine phosphatases, PTP) and readers (Src homology 2, SH2; phosphotyrosine-binding domain, PTB) in humans. PTB (green) and SH2 (light blue) domain both contain a pTyr binding pocket (yellow circle), yet specificity is determined by a secondary binding site adjacent to the pTyr binding pocket that recognize sequences surrounding the pTyr. (b) The total number of PTK, classical PTPs (total number of tyrosine phosphatases) and SH2-encoded genes across eukaryotes. The branched divergence times and lengths in millions of years (Ma) are indicated.
Figure 2.
Figure 2.
Primordial function of SH2 domains and pTyr signalling. (a) The ribbon structure of the yeast Spt6 tandem SH2 (left panel, PBD: 3PJP). The charged surface of the tandem SH2 (right) indicates the positions of negative (red) and positive charge (blue) of the tandem SH2 domain. Highlighted in the yellow circle is the phospho-binding pocket for pSer. (b) The SH2 domain transcriptional activator STAT (red) is present as early as Dictyostelium and found in humans. Analogous to mammalian STAT signalling, STATc is regulated by tyrosine phosphorylation (yellow dot) through PTKs (green) and PTPs (blue). In Dictyostelium, the SH2/RING domain containing protein CblA (orange) antagonizes the phosphastase, while in mammals Cbl inhibits the PTK Jak.
Figure 3.
Figure 3.
The gain and loss of SH2 and PTK families in Eukaryota. The eukaryotic tree is shown with the phylum and genus species listed on the right. The number of SH2/PTK families are listed in black text with the gain and loss indicated in grey text. The 38 SH2 and 29 PTK families represent those that are found in humans and are present in other lower eukaryotes [8,10,34].
Figure 4.
Figure 4.
Emergence and expansion of SH2 and PTK families. The presence and absence of conserved families of SH2 and PTK proteins is indicated for representative species covering the unikont branch from social amoeba/slime mould Dictyostelium species to H. sapiens. The families of SH2 and PTK were identified previously [8,10,34]. Text colour indicates SH2 families that lack a TK domain (black), RTK families (orange), CTKs containing an SH2 domain (blue) and CTKs that lack an SH2 domain (green). The general domain organization of each family is shown on the right.
Figure 5.
Figure 5.
Fates of duplicate genes. (a) When a new duplicate arises it is eliminated in a majority of cases as fixation in a population is rare event. After fixation, the gene can undergo three general fates that include: neofunctionalization, where a duplicate copy acquires a novel function; non-functionalization of a gene through mutation of its promoter and/or mutation of its function creating a pseudogene by inactivation; and subfunctionalization that divides the primary ancestral function between the duplicate copies possibly across distinct tissue types. (b) Duplicate copies of genes can diverge through means of evolving novel protein domain specificity for ligands, gain or loss of a protein domain, insertion or deletion of short linear motifs and lastly an alteration in the promoter of the gene allowing for specialized tissue expression and transcription control.
Figure 6.
Figure 6.
Evolution of protein domain specificity. (a) The specificity of a protein interaction domain, such as an SH2 domain, can either change or remain conserved over time. Conservation of peptide ligand specificity pocket allows interactions to be conserved throughout evolution. Insertion of linear motifs and evolving novel binding sites can allow for an SH2 domain to recognize multiple binding partners. Specificity can also evolve for a domain, yet this can result in acquiring a completely new set of binding partners while the ancient partners are lost. Lastly, a domain can coevolve over time to maintain ancient binding partners but also evolve novel binding partners by evolving its peptide-binding pocket. A protein domain can become inactivated through mutations of its binding pocket such that it no longer can recognize any of its original ligands. (b) SH2 domains use sequence context and non-permissive residues to discriminate pTyr peptide ligands. This underlies a wider channel for information flow between the ligand and the SH2 domain. For example, the SH2 domains of Brk and Crk can each engage a subset of peptides containing a Pro or Leu at +3 (three residues C-terminus to pTyr; left panel): Brk and Crk distinguish between peptides containing a +3 Pro through distinct recognition of permissive and non-permissive residues at +1 and +4. Brk SH2-domain binding is favoured with permissive factors for Brk (+1 Glu and +4 Glu), which are also non-permissive factors for Crk favour Brk binding (middle panel). A +1 Asp and +4 Arg favours Crk binding over Brk (right panel). This is suggestive of coevolution between SH2 domains and peptide ligands to maximize specific recognition events using available peptide sequence information. (c) The adaptor Grb2 protein contains two SH3 domains (N-SH3, C-SH3) and a central SH2 domain. The sequence alignment of the GRB2 family from C. elegans to H. sapiens was mapped onto the structure of each individual domain. The percentage sequence conservation of the three domains is represented as a heat map on the surface of the solved ligand-bound structures (see legend for percentage of conservation). Structures used to highlight conservation are PDB: 1BMB; PDB: 2W0Z; PDB: 1GBR.
Figure 7.
Figure 7.
Evolution of a short linear motif within the SH2 domain of Crk to accommodate the interaction with the SH3 domain of Abl kinase. (a) Overlay of Crk SH2 domain structures from multiple organisms. The structures are coloured according to the different organisms in (b). The intramolecular pTyr peptide ligand of Crk (Y221) is shown in grey. (b) The SH2 domain structures from D. melanogaster (Dm), S. purpuratas (Sp), C. intestinalis (Ci), D. rerio (Dr), X. tropicalis (Xt), G. gallus (Gg), M. musculus (Mm), R. norvegicus (Rt), M. domestica (Md), B. taurus (Bt) were modelled using Swiss-model and UCSF-Chimera of the H. sapiens (Hs) Crk SH2 domain, PDB: 1JU5 (see Liu et al. [8] for detailed methods). (c) Sequence alignment of the DE loop of Crk and CrkL orthologues is shown. The presence of a splice site within the DE loop (circled in red) in Crk and absent in CrkL orthologues provides an opportunity for evolving an extended SH3 binding loop.
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