Abstract
Src homology 2 (SH2) domains play a critical role in signal transduction in mammalian cells by binding to phosphorylated Tyr (pTyr). Apart from a few isolated cases in viruses, no functional SH2 domain has been identified to date in prokaryotes. Here we identify 93 SH2 domains from Legionella that are distinct in sequence and specificity from mammalian SH2 domains. The bacterial SH2 domains are not only capable of binding proteins or peptides in a Tyr phosphorylation-dependent manner, some bind pTyr itself with micromolar affinities, a property not observed for mammalian SH2 domains. The Legionella SH2 domains feature the SH2 fold and a pTyr-binding pocket, but lack a specificity pocket found in a typical mammalian SH2 domain for recognition of sequences flanking the pTyr residue. Our work expands the boundary of phosphotyrosine signalling to prokaryotes, suggesting that some bacterial effector proteins have acquired pTyr-superbinding characteristics to facilitate bacterium-host interactions.
Highlights
Src homology 2 (SH2) domains play a critical role in signal transduction in mammalian cells by binding to phosphorylated Tyr
While both Legionella SH2 domains feature a defined pTyr-binding pocket, they are devoid of a second pocket or binding site for a C-terminal residue to the pTyr that is commonly found in a mammalian SH2 domain
A functional SH2 domain has not been identified in bacteria to date, though genomic analysis has predicted the existence of SH2 domain-containing effectors in Legionella[11,13]
Summary
Src homology 2 (SH2) domains play a critical role in signal transduction in mammalian cells by binding to phosphorylated Tyr (pTyr). Because the SH2 superbinder, when introduced into mammalian cells, was capable of inhibiting tyrosine kinase signaling, we wondered if pathogenic bacteria would exploit this mechanism to gain an advantage when infecting a host. To explore this notion, we conducted an exhaustive search of the bacteria genome database and identified 93 putative SH2 domains in 84 Legionella proteins. We characterized 13 Legionella SH2 domains for ability to bind pTyr-containing peptides and found 11 were capable of binding to the pTyr residue and to mammalian proteins in a Tyr phosphorylation-dependent manner. Our findings, which expand the realm of the SH2 domain from eukaryotes to prokaryotes, imply that the tyrosine kinase–pTyr–SH2 signaling axis may play an important role in the Legionella-host interaction and pathophysiology of the Legionnaires’ disease
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