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Protein-protein interactions drive functions in eukaryotes that can be described by short linear motifs (SLiMs). Conservation of SLiMs help illuminate functional SLiMs in eukaryotic protein families. However, the simplicity of eukaryotic SLiMs makes them appear by chance due to mutational processes not only in eukaryotes but also in pathogenic bacteria and viruses. Further, functional eukaryotic SLiMs are often found in disordered regions. Although proteomes from pathogenic bacteria and viruses have less disorder than eukaryotic proteomes, their proteins can successfully mimic eukaryotic SLiMs and disrupt host cellular function. Identifying important SLiMs in pathogens is difficult but essential for understanding potential host-pathogen interactions. We performed a comparative analysis of structural features for experimentally verified SLiMs from the Eukaryotic Linear Motif (ELM) database across viruses, bacteria, and eukaryotes. Our results revealed that many viral SLiMs and specific motifs found across viruses and eukaryotes, such as some glycosylation motifs, have less disorder. Analyzing the disorder and coil properties of equivalent SLiMs from pathogens and eukaryotes revealed that some motifs are more structured in pathogens than their eukaryotic counterparts and vice versa. These results support a varying mechanism of interaction between pathogens and their eukaryotic hosts for some of the same motifs.

Most viruses have small genomes that encode proteins needed to perform essential enzymatic functions. Across virus families, primary enzyme functions are under functional constraint; however, secondary functions mediated by exposed protein surfaces that promote interactions with the host proteins may be less constrained. Viruses often form transient interactions with host proteins through conformationally flexible interfaces. Exposed flexible amino acid residues are known to evolve rapidly suggesting that secondary functions may generate diverse interaction potentials between viruses within the same viral family. One mechanism of interaction is viral mimicry through short linear motifs (SLiMs) that act as functional signatures in host proteins. Viral SLiMs display specific patterns of adjacent amino acids that resemble their host SLiMs and may occur by chance numerous times in viral proteins due to mutational and selective processes. Through mimicry of SLiMs in the host cell proteome, viruses can interfere with the protein interaction network of the host and utilize the host-cell machinery to their benefit. The overlap between rapidly evolving protein regions and the location of functionally critical SLiMs suggest that these motifs and their functional potential may be rapidly rewired causing variation in pathogenicity, infectivity, and virulence of related viruses. The following review provides an overview of known viral SLiMs with select examples of their role in the life cycle of a virus, and a discussion of the structural properties of experimentally validated SLiMs highlighting that a large portion of known viral SLiMs are devoid of predicted intrinsic disorder based on the viral SLiMs from the ELM database.