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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.

Various structural and functional constraints govern the evolution of protein sequences. As a result, the relative rates of amino acid replacement among sites within a protein can vary significantly. Previous large-scale work on Metazoan (Animal) protein sequence alignments indicated that amino acid replacement rates are partially driven by a complex interaction among three factors: intrinsic disorder propensity, secondary structure, and functional domain involvement. Here, we use sequence-based predictors to evaluate the effects of these factors on site-specific sequence evolutionary rates within four eukaryotic lineages: Metazoans, Plants, Saccharomycete Fungi, and Alveolate Protists. Our results show broad, consistent trends across all four Eukaryote groups. In all four lineages, there is a significant increase in amino acid replacement rates when comparing: (i) disordered vs. ordered sites, (ii) random coil sites vs. sites in secondary structures, and (iii) inter-domain linker sites vs. sites in functional domains. Additionally, within Metazoans, Plants, and Saccharomycetes, there is a strong confounding interaction between intrinsic disorder and secondary structure&mdash, alignment sites exhibiting both high disorder propensity and involvement in secondary structures have very low average rates of sequence evolution. Analysis of gene ontology (GO) terms revealed that in all four lineages, a high fraction of sequences containing these conserved, disordered-structured sites are involved in nucleic acid binding. We also observe notable differences in the statistical trends of Alveolates, where intrinsically disordered sites are more variable than in other Eukaryotes and the statistical interactions between disorder and other factors are less pronounced.