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

## TL;DR

Bacterial proteins like SteE can change the activity of a host kinase, GSK3, by mimicking eukaryotic signaling motifs, enhancing bacterial virulence.

## Contribution

The discovery that SteE and its homologues use mimicry of eukaryotic motifs to reprogram GSK3 kinase activity.

## Key findings

- SteE and its homologues from various Gram-negative pathogens mediate kinase reprogramming of GSK3.
- An L/xGxP motif in SteE is essential for GSK3's tyrosine-directed activity.
- Short linear motifs in SteE mimic eukaryotic signaling motifs to enable kinase reprogramming.

## Abstract

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.

A virulence protein from diverse bacteria switches the amino acid specificity of the eukaryotic kinase GSK3. This kinase reprogramming depends on several short linear motifs that each appear to mimic eukaryotic signalling motifs.

Putative bacterial homologues of Salmonella effector SteE mediate kinase reprogramming of eukaryotic GSK3.Mimicry of several short linear motifs underpins the molecular basis of kinase reprogramming by SteE.An L/xGxP motif within SteE mediates tyrosine-directed activity.Effectors like SteE restore this dual specificity of GSK3 and exploit it for trans-phosphorylation of a neosubstrate.

Putative bacterial homologues of Salmonella effector SteE mediate kinase reprogramming of eukaryotic GSK3.

Mimicry of several short linear motifs underpins the molecular basis of kinase reprogramming by SteE.

An L/xGxP motif within SteE mediates tyrosine-directed activity.

Effectors like SteE restore this dual specificity of GSK3 and exploit it for trans-phosphorylation of a neosubstrate.

A virulence protein from diverse bacteria switches the amino acid specificity of the eukaryotic kinase GSK3. This kinase reprogramming depends on several short linear motifs that each appear to mimic eukaryotic signalling motifs.