Bacterial effectors mediate kinase reprogramming through mimicry of conserved eukaryotic motifs.

Bacteria have evolved numerous biochemical processes that underpin their biology and pathogenesis. The small, non-enzymatic bacterial (Salmonella) effector SteE mediates kinase reprogramming, whereby the canonical serine/threonine host kinase GSK3 gains tyrosine-directed activity towards neosubstrates, promoting Salmonella virulence. Yet, both the mechanism behind the switch in GSK3's activity and the diversity of this phenomenon remain to be determined. Here we show that kinase reprogramming of GSK3 is mediated by putative homologues from diverse Gram-negative pathogens. Next, we identify both the molecular basis of how SteE targets GSK3 and uncover that the SteE-induced tyrosine activity conferred on GSK3 requires an L/xGxP motif. This motif, found in several CMGC kinases that undergo auto-tyrosine phosphorylation, was previously shown to mediate GSK3 autophosphorylation on a tyrosine. Together, we suggest that the SteE family of intrinsically disordered proteins mediates kinase reprogramming via several short linear motifs that each appear to mimic eukaryotic signalling motifs. With this insight comes the potential for the rationale design of synthetic reprogramming proteins.