Potential of known and short prokaryotic protein motifs as a basis for novel peptide-based antibacterial therapeutics: a computational survey

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.

<i>In Silico</i> Structural and Functional Annotation of Nine Essential Hypothetical Proteins from <i>Streptococcus pneumoniae</i>

“…This finding strengthens the suggestion on the possibility of SPD_1333 to be a membrane protein because dilysine motif plays a role in conferring the localization of this kind of protein [40]. Many types of motifs, including the dilysine motif, are known to mimic eukaryotic motifs, thus enabling pathogenic bacteria to disturb host's cellular functions [41]. From this, it is suggested that the ability of SPD_1333 to bind with dilysine motifcontaining molecule may give benefit to this protein in accomplishing its virulence mission inside the host.…”

Searching Algorithm for Type IV Effector proteins (S4TE) 2.0: improved tools for type IV effector prediction, analysis and comparison

“…There are two classes of NLS, monopartite and Bipartite. In S4TE 2.0, the search for monopartite NLS has been improved according to Ruhanen et al [6]. We rewrote this module to add more known NLS motifs in the search.…”

A Tale of Effectors; Their Secretory Mechanisms and Computational Discovery in Pathogenic, Non-Pathogenic and Commensal Microbes

“…IPIO effector or some proteins/peptides with an RGD motif interact with adhesion between cell wall and plasma membrane leading to disruption of plant cells. The motifs composed of less than 10 amino acids, called short linear motifs (SliMs) enable pathogenic bacteria to control intracellular process of host [51]. The cell wall peptidoglycan of Gram positive bacteria act as surface organelle for transport and assembly of many proteins which interact with hosts.…”