Resources to Discover and Use Short Linear Motifs in Viral Proteins

Viral proteins evade host immune function by molecular mimicry, often achieved by short linear motifs (SLiMs) of three to ten consecutive amino acids (AAs). Motif mimicry tolerates mutations, evolves quickly to modify interactions with the host, and enables modular interactions with protein complexes. Host cells cannot easily coordinate changes to conserved motif recognition and binding interfaces under selective pressure to maintain critical signaling pathways. SLiMs offer potential for use in synthetic biology, such as better immunogens and therapies, but may also present biosecurity challenges. We survey viral uses of SLiMs to mimic host proteins, and information resources available for motif discovery. As the number of examples continues to grow, knowledge management tools are essential to help organize and compare new findings. •Short linear motifs (SLiMs) are patterns of three to ten consecutive AAs used by eukaryotic cells for tasks that include: signaling, localization, degradation, and proteolytic cleavage.•Viruses use SLiMs to their advantage, including interference with antiviral innate immune pathways.•Viral SLiMs can tolerate mutations, evolve quickly to modify host interactions, and co-occur in a modular manner or involve multiprotein complexes.•SLiMs are useful in synthetic biology, where minor edits can alter target specificity, modulate persistence, reprogram interactions with cell-signaling domains, and alter protein function in myriad other ways.•Aside from possible beneficial uses, for example, to produce better immunogens and develop therapeutic interventions against infectious disease, SLiMs may help characterize new and emerging threats to global health.