Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

Abstract

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.

Rapidly evolving viral motifs mostly target biophysically constrained binding pockets of host proteins

“…The result of this filtration was a set of 5,064 unique human-virus PPIs that are inferred to be mediated by a viral-mimicking motif, embedded within a disordered region, and a human PRD (see Figure S2 for a scheme of this workflow). We note that in some cases functional ELMs may be found in relatively structured surface regions (Elkhaligy et al, 2021;Hagai et al, 2011), such as in the case of glycosylation sites. However, we here choose to use a strict threshold and analyze a smaller subset of inferred motifs to obtain fewer false positives.…”

Rapidly evolving viral motifs target biophysically constrained binding pockets of host proteins

“…The result of this filtration was a set of 5,064 unique host-virus PPIs that are inferred to be mediated by a viral-mimicking motif, embedded within a disordered region, and a host PRD (see Supp Fig 1 for a scheme of this workflow). We note that in some cases functional ELMs may be found in relatively structured surface regions 59,60 , such as in the case of glycosylation sites. However, we here choose to use a strict threshold and analyze a smaller subset of inferred motifs to have fewer false positives.…”

Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs

“…Viruses hijack and deregulate the host cell machinery through virus-host protein-protein interactions (PPIs) that often involve interactions between folded host proteins and viral short linear motifs (SLiMs) (Davey et al, 2011). SLiMs are compact and degenerate protein interaction modules, typically encoded in protein regions between three to ten amino acids in length and often, but not always, found in intrinsically disordered regions (IDRs) of proteins (Elkhaligy et al, 2021; Kumar et al, 2022). SLiM-based hijacking has been reported for all stages of viral infection, including viral cell entry, replication, assembly, release, and subversion of the cellular defense response (Davey et al, 2011; Kadaveru et al, 2008).…”