Abstract
Intrinsically disordered regions in eukaryotic proteomes contain key signaling and regulatory modules and mediate interactions with many proteins. Many viral proteomes encode disordered proteins and modulate host factors through the use of short linear motifs (SLiMs) embedded within disordered regions. However, the degree of viral protein disorder across different viruses is not well understood, so we set out to establish the constraints acting on viruses, in terms of their use of disordered protein regions. We surveyed predicted disorder across 2,278 available viral genomes in 41 families, and correlated the extent of disorder with genome size and other factors. Protein disorder varies strikingly between viral families (from 2.9% to 23.1% of residues), and also within families. However, this substantial variation did not follow the established trend among their hosts, with increasing disorder seen across eubacterial, archaebacterial, protists, and multicellular eukaryotes. For example, among large mammalian viruses, poxviruses and herpesviruses showed markedly differing disorder (5.6% and 17.9%, respectively). Viral families with smaller genome sizes have more disorder within each of five main viral types (ssDNA, dsDNA, ssRNA+, dsRNA, retroviruses), except for negative single-stranded RNA viruses, where disorder increased with genome size. However, surveying over all viruses, which compares tiny and enormous viruses over a much bigger range of genome sizes, there is no strong association of genome size with protein disorder. We conclude that there is extensive variation in the disorder content of viral proteomes. While a proportion of this may relate to base composition, to extent of gene overlap, and to genome size within viral types, there remain important additional family and virus-specific effects. Differing disorder strategies are likely to impact on how different viruses modulate host factors, and on how rapidly viruses can evolve novel instances of SLiMs subverting host functions, such as innate and acquired immunity.
Highlights
The majority of enzymatic and structural viral proteins have defined tertiary structure, but it has emerged over the last number of years that many functions vital for competent viral infection, in terms of host interactions, are mediated by protein regions that lack defined tertiary structure in their native state [1,2,3,4,5,6,7,8,9] Their interactions may be mediated by short linear protein motifs (SLiMs) [10] and other recognition domains [11,12] embedded within the disordered region by longer disordered interfaces referred to as disordered domains [13], or by combinations of motifs and disordered domains [14,15]
We focused on predictions within proteins rather than within precursor polyproteins, noting that the overall survey results were very strongly correlated, regardless which way the analysis was completed (Fig S3)
We noted that viral genomes have a strikingly high variability in intrinsic disorder, ranging from 0.5–48.5% (Fig. 1 and Fig. 2)
Summary
The majority of enzymatic (e.g. proteases) and structural (e.g. capsid proteins) viral proteins have defined tertiary structure, but it has emerged over the last number of years that many functions vital for competent viral infection, in terms of host interactions, are mediated by protein regions that lack defined tertiary structure in their native state [1,2,3,4,5,6,7,8,9] Their interactions may be mediated by short linear protein motifs (SLiMs) [10] and other recognition domains [11,12] embedded within the disordered region by longer disordered interfaces referred to as disordered domains [13], or by combinations of motifs and disordered domains [14,15]. Disordered regions may in some [16], but not all, cases form a secondary structure on binding to their interaction partner. In their utilization of disordered proteins, viruses resemble cellular organisms, in particular eukaryotes, which make extensive use of disordered proteins [17,18,19,20,21]. The use of compact interfaces allows increased redundancy by allowing functionality to be mediated by a set of short disordered regions (e.g. the Late domains of retroviral Gag proteins) rather than on a single globular interface, resulting in increased evolutionary robustness of viral proteins [10] a deeper understanding of the role of intrinsically disordered regions in viruses is important if we are to fully understand the
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