Abstract
Short linear motifs (SLiMs) are functional stretches of protein sequence that are of crucial importance for numerous biological processes by mediating protein–protein interactions. These motifs often comprise peptides of less than 10 amino acids that modulate protein–protein interactions. While well-characterized in eukaryotic intracellular signaling, their role in prokaryotic signaling is less well-understood. We surveyed the distribution of known motifs in prokaryotic extracellular and virulence proteins across a range of bacterial species and conducted searches for novel motifs in virulence proteins. Many known motifs in virulence effector proteins mimic eukaryotic motifs and enable the pathogen to control the intracellular processes of their hosts. Novel motifs were detected by finding those that had evolved independently in three or more unrelated virulence proteins. The search returned several significantly over-represented linear motifs of which some were known motifs and others are novel candidates with potential roles in bacterial pathogenesis. A putative C-terminal G[AG].$ motif found in type IV secretion system proteins was among the most significant detected. A KK$ motif that has been previously identified in a plasminogen-binding protein, was demonstrated to be enriched across a number of adhesion and lipoproteins. While there is some potential to develop peptide drugs against bacterial infection based on bacterial peptides that mimic host components, this could have unwanted effects on host signaling. Thus, novel SLiMs in virulence factors that do not mimic host components but are crucial for bacterial pathogenesis, such as the type IV secretion system, may be more useful to develop as leads for anti-microbial peptides or drugs.
Highlights
Short linear motifs (SLiMs) are functional microdomains in proteins that play a critical role in many distinct biological processes such as cell signaling and regulation, post-translational modifications, proteolytic cleavage, and protein trafficking (Davey et al, 2011b; Mooney et al, 2012)
Since pathogenesis proteins from bacteria often interact with host protein components, we examined whether any of the identified motifs showed similarity to known eukaryotic linear motifs, using the Comparimotif tool
Attack, the evolutionary plasticity of such motifs in both bacteria (Figure 3) and in hosts (Neduva and Russell, 2005) suggest that bacteria can rapidly evolve alternative effector strategies to replace one targeted host component with another. Where such drugs are developed for other indications in treating non-infectious disease, they may have an impact on bacterial pathogenesis and would certainly be worth investigating
Summary
Short linear motifs (SLiMs) are functional microdomains in proteins that play a critical role in many distinct biological processes such as cell signaling and regulation, post-translational modifications, proteolytic cleavage, and protein trafficking (Davey et al, 2011b; Mooney et al, 2012). These motifs are typically found in eukaryotic disordered protein regions and vary in size from 3 to 12 amino acids (Fuxreiter et al, 2007). SLiMs have less than five defined amino acid positions and frequently these positions have some degree of flexibility in amino acid composition Their shortness makes them evolutionarily plastic, allowing them to evolve convergently in unrelated proteins. Their short length presents a challenge for SLiM discovery both experimentally and computationally, since there may be many false positive findings using both methods
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