Use of Host-like Peptide Motifs in Viral Proteins Is a Prevalent Strategy in Host-Virus Interactions

Abstract

Virus interact extensively with host proteins, but the mechanisms controlling these interactions are not well understood. We present a comprehensive analysis of eukaryotic linear-peptide motifs (ELMs) in 2,208 viral genomes and reveal that viruses exploit molecular mimicry of host-like ELMs to possibly assist in host-virus interactions. Using a statistical genomics approach, we identify a large number of potentially functional ELMs and observe that the occurrence of ELMs is often evolutionarily conserved but not uniform across virus families. Some viral proteins contain multiple types of ELMs, in striking similarity to complex regulatory modules in host proteins, suggesting that ELMs may act combinatorially to assist viral replication. Furthermore, a simple evolutionary model suggests that the inherent structural simplicity of ELMs often enables them to tolerate mutations and evolve quickly. Our findings suggest that ELMs may allow fast rewiring of host-virus interactions, which likely assists rapid viral evolution and adaptation to diverse environments.

Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300

“…Intrinsically disordered proteins are highly abundant in viral proteomes (83) and are utilized by viruses to mimic cellular IDR motifs and as hubs or scaffolds to rewire cellular signaling networks (11,84,85). Given the role that CBP and p300 play in the regulation of critical cellular signaling and transcriptional networks, it is perhaps not surprising that they are targeted by numerous viral proteins (12,86).…”

Pathogen mimicry of host protein-protein interfaces modulates immunity

“…Several viruses have homologs of short amino acid sequences instead of the whole proteins or domains, known as (sequence) motif mimicry [27,49]. Short linear motifs (SLIMs), which are generally composed of 3-10 residues, were proposed to have important roles in pathway modification (functional switching) fitting well our description.…”

“…To circumvent antiviral host immune responses, pathogens espoused two audacious strategies that enable molecular mimicry: horizontal gene transfer (HGT, also known as lateral gene transfer) through which the pathogens acquire host genes and sculpt them over time to perform new functions, and convergent evolution through which the pathogen and host evolved independently and ended up with the similar structures or functions (or chemical properties) [10,27]. In HGT, both the sequence and the structure of the homologs are similar.…”

Mx1 and Mx2 key antiviral proteins are surprisingly lost in toothed whales

“…It is compelling to consider what events drove Mx loss in this clade of highly social marine mammals. Although other forces and scenarios cannot be ruled out (33), an intriguing hypothesis is that the loss enabled the survival of Odontoceti ancestors from a virus that took advantage of Mx function, possibly through direct interaction with the Mx proteins [e.g., human individuals and cells that inactivate the CCR5 gene are resistant to HIV-1 infection (34)], or through mimicry of the Mx proteins (35). Because herpes simplex virus 1 (HSV-1) has been shown to enhance infection by inducing an alternative splice variant of Mx1 omitting exons 10-12, and because alphaherpesviruses closely related to HSV-1 still infect dolphins today, an ancestor of HSV-1 is one possible candidate pathogen for this theory (2,3,36).…”